bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired Myocardial Mitochondrial Function in an Experimental Model of Anaphylactic Shock
Authors: Oulehri Walid , Collange Olivier , Tacquard Charles , Bellou Abdelouahab , Graff Julien , Charles Anne-Laure , Geny Bernard , Mertes Paul-Michel
Published: May 2022

Anaphylactic shock (AS) is associated with a profound vasodilation and cardiac dysfunction. The cellular mechanisms underlying AS-related cardiac dysfunction are unknown. We hypothesized that myocardial mitochondrial dysfunction may be associated with AS cardiac dysfunction. In controls and sensitized Brown Norway rats, shock was induced by ovalbumin i.v bolus, and abdominal aortic blood flow (ABF), systemic mean arterial pressure (MAP), and lactatemia were measured for 15 min. Myocardial mitochondrial function was assessed with the evaluation of mitochondrial respiration, oxidative stress production by reactive oxygen species (ROS), reactive nitrogen species (RNS), and the measurement of superoxide dismutases (SODs) activity. Oxidative damage was assessed by lipid peroxidation. The mitochondrial ultrastructure was assessed using transmission electronic microscopy. AS was associated with a dramatic drop in ABF and MAP combined with a severe hyperlactatemia 15 min after shock induction. CI-linked substrate state (197 ± 21 vs. 144 ± 21 pmol/s/mg, p < 0.05), OXPHOS activity by complexes I and II (411 ± 47 vs. 246 ± 33 pmol/s/mg, p < 0.05), and OXPHOS activity through complex II (316 ± 40 vs. 203 ± 28 pmol/s/mg, p < 0.05) were significantly impaired. ROS and RNS production was not significantly increased, but SODs activity was significantly higher in the AS group (11.15 ± 1.02 vs. 15.50 ± 1.40 U/mL/mg protein, p = 0.02). Finally, cardiac lipid peroxidation was significantly increased in the AS group (8.50 ± 0.67 vs. 12.17 ± 1.44 µM/mg protein, p < 0.05). No obvious changes were observed in the mitochondrial ultrastructure between CON and AS groups. Our experimental model of AS results in rapid and deleterious hemodynamic effects and was associated with a myocardial mitochondrial dysfunction with oxidative damage and without mitochondrial ultrastructural injury.
Co-Occurrence of Interleukin-6 Receptor Asp358Ala Variant and High Plasma Levels of IL-6: An Evidence of IL-6 Trans-Signaling Activation in Deep Vein Thrombosis (DVT) Patients
Authors: Salemi Rossella , Gattuso Giuseppe , Tomasello Barbara , Lavoro Alessandro , Gaudio Agostino , Libra Massimo , Signorelli Salvatore Santo , Candido Saverio
Published: May 2022

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in several mechanisms, and the alteration of IL-6 signaling leads to the overactivation of various processes including immunity, inflammation, and hemostasis. Although IL-6 increase has been documented in venous thromboembolic diseases, the exact involvement of IL-6 signaling in deep vein thrombosis (DVT) has not been fully understood. Consequently, we investigated the involvement of IL-6 trans-signaling in inflammatory events occurring in DVT, focusing on the role of the interleukin-6 receptor (IL6-R) Asp358Ala variant. The circulating levels of IL-6, soluble IL6-R (sIL6-R), and soluble glycoprotein 130, as well as the Asp358Ala genotyping, were assessed in a consecutive cohort of DVT patients and healthy controls. The results indicated that IL-6 was higher in DVT compared to controls. Moreover, sIL6-R levels were strongly correlated to Asp358Ala variant in both groups, showing a high frequency of this mutation across all samples. Interestingly, our results showed a high frequency of both Asp358Ala mutation and raised IL-6 levels in DVT patients (OR = 21.32; p ≤ 0.01), highlighting that this mutation could explain the association between IL-6 overactivation and DVT outcome. Overall, this study represents a proof of concept for the targeting of IL-6 trans-signaling as a new strategy for the DVT adjuvant therapy.
The Interplay between Vitamin D, Exposure of Anticholinergic Antipsychotics and Cognition in Schizophrenia
Authors: Gaebler Arnim Johannes , Finner-Prével Michelle , Sudar Federico Pacheco , Langer Felizia Hannah , Keskin Fatih , Gebel Annika , Zweerings Jana , Mathiak Klaus
Published: May 2022

Vitamin D deficiency is a frequent finding in schizophrenia and may contribute to neurocognitive dysfunction, a core element of the disease. However, there is limited knowledge about the neuropsychological profile of vitamin D deficiency-related cognitive deficits and their underlying molecular mechanisms. As an inductor of cytochrome P450 3A4, a lack of vitamin D might aggravate cognitive deficits by increased exposure to anticholinergic antipsychotics. This cross-sectional study aims to assess the relationship between 25-OH-vitamin D-serum concentrations, anticholinergic drug exposure and neurocognitive functioning (Brief Assessment of Cognition in Schizophrenia, BACS, and Trail Making Test, TMT) in 141 patients with schizophrenia. The anticholinergic drug exposure was estimated by adjusting the concentration of each drug for its individual muscarinic receptor affinity. Using regression analysis, we observed a positive relationship between vitamin D levels and processing speed (TMT-A and BACS Symbol Coding) as well as executive functioning (TMT-B and BACS Tower of London). Moreover, a negative impact of vitamin D on anticholinergic drug exposure emerged, but the latter did not significantly affect cognition. When other cognitive items were included as regressors, the impact of vitamin D remained only significant for the TMT-A. Among the different cognitive impairments in schizophrenia, vitamin D deficiency may most directly affect processing speed, which in turn may aggravate deficits in executive functioning. This finding is not explained by a cytochrome P450-mediated increased exposure to anticholinergic antipsychotics.
Strategy to Enhance Anticancer Activity and Induced Immunogenic Cell Death of Antimicrobial Peptides by Using Non-Nature Amino Acid Substitutions
Authors: Cheah Yu-Huan , Liu Chun-Yu , Yip Bak-Sau , Wu Chih-Lung , Peng Kuang-Li , Cheng Jya-Wei
Published: May 2022

There is an urgent and imminent need to develop new agents to fight against cancer. In addition to the antimicrobial and anti-inflammatory activities, many antimicrobial peptides can bind to and lyse cancer cells. P-113, a 12-amino acid clinically active histatin-rich peptide, was found to possess anti-Candida activities but showed poor anticancer activity. Herein, anticancer activities and induced immunogenic cancer cell death of phenylalanine-(Phe-P-113), β-naphthylalanine-(Nal-P-113), β-diphenylalanine-(Dip-P-113), and β-(4,4′-biphenyl)alanine-(Bip-P-113) substituted P-113 were studied. Among these peptides, Nal-P-113 demonstrated the best anticancer activity and caused cancer cells to release potent danger-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS), cytochrome c, ATP, and high-mobility group box 1 (HMGB1). These results could help in developing antimicrobial peptides with better anticancer activity and induced immunogenic cell death in therapeutic applications.
Establishment of a Tissue-Mimicking Surrogate for Pulmonary Lesions to Improve the Development of RFA Instruments and Algorithms
Authors: Bühler Louisa , Enderle Markus D. , Kahn Nicolas , Polke Markus , Schneider Marc A. , Heußel Claus Peter , Herth Felix J. F. , Linzenbold Walter
Published: May 2022

(1) Development of radiofrequency ablation (RFA) systems for pulmonary lesions is restricted by availability of human tumor specimens and limited comparability of animal tissue. We aimed to develop a new surrogate tissue overcoming these drawbacks. (2) Reference values for electrical impedance in lung tumor tissue were collected during routine lung tumor RFA (n = 10). Subsequently, a tissue-mimicking surrogate with comparable electrical impedance and facilitating detection of the ablation margins was developed. (3) The mean electrical impedance for all patients was 103.5 ± 14.7 Ω. In the optimized surrogate tissue model consisting of 68% agar solution, 23% egg yolk, 9% thermochromic ink, and variable amounts of sodium chloride, the mean electrical impedance was adjustable from 74.3 ± 0.4 Ω to 183.2 ± 5.6 Ω and was a function (y = 368.4x + 175.2; R2 = 0.96; p < 0.001) of sodium chloride concentration (between 0 and 0.3%). The surrogate tissue achieved sufficient dimensional stability, and sample cuts revealed clear margins of color change for temperatures higher 60 °C. (4) The tissue-mimicking surrogate can be adapted to lung tumor with respect to its electrical properties. As the surrogate tissue allows for simple and cost-effective manufacturing, it is suitable for extensive laboratory testing of RFA systems for pulmonary ablation.
A Differentiable Dynamic Model for Musculoskeletal Simulation and Exoskeleton Control
Authors: Kuo Chao-Hung , Chen Jia-Wei , Yang Yi , Lan Yu-Hao , Lu Shao-Wei , Wang Ching-Fu , Lo Yu-Chun , Lin Chien-Lin , Lin Sheng-Huang , Chen Po-Chuan , Chen You-Yin
Published: May 2022

An exoskeleton, a wearable device, was designed based on the user’s physical and cognitive interactions. The control of the exoskeleton uses biomedical signals reflecting the user intention as input, and its algorithm is calculated as an output to make the movement smooth. However, the process of transforming the input of biomedical signals, such as electromyography (EMG), into the output of adjusting the torque and angle of the exoskeleton is limited by a finite time lag and precision of trajectory prediction, which result in a mismatch between the subject and exoskeleton. Here, we propose an EMG-based single-joint exoskeleton system by merging a differentiable continuous system with a dynamic musculoskeletal model. The parameters of each muscle contraction were calculated and applied to the rigid exoskeleton system to predict the precise trajectory. The results revealed accurate torque and angle prediction for the knee exoskeleton and good performance of assistance during movement. Our method outperformed other models regarding the rate of convergence and execution time. In conclusion, a differentiable continuous system merged with a dynamic musculoskeletal model supported the effective and accurate performance of an exoskeleton controlled by EMG signals.
Development of a Linear Immobilization Carrier-Based Immunoassay for Aflatoxin
Authors: Yan Honglin , Tang Xiaoqian , Liu Xiaohan , Zheng Yating , Zhang Minhui , Zhao Yueju , Zhang Qi
Published: May 2022

We explored the feasibility of developing immunoassay technology with a linear carrier, to develop a simpler and cheaper rapid immunoassay technology. We selected aflatoxins as an example for research, as they are a group of highly toxic and carcinogenic compounds representing a worldwide threat to human health and life. With a non-competitive immunoassay, we detected and evaluated the effect of 28 different linear materials on antibody immobilization. Mercerized cotton and Dyneema line were chosen from the linear materials for further comparison using a competitive immunoassay, because both showed high-signal values and relatively low background noise. The results showed the sensitive IC50 of mercerized cotton as the reaction carrier was 0.33 ng/mL, and the linear range was 0.16~3.25 ng/mL. The sensitivity using Dyneema line as the reaction carrier was 1.16 ng/mL. The competitive curves of four sample matrices were established to evaluate the stability of the detection system; these were basically consistent with those without sample matrices. In conclusion, both mercerized cotton and Dyneema, will be suggested for the novel development of linear immobilization carrier-based immunoassays for other analytes, and especially to construct inexpensive and easy-to-obtain biological and environmental analytical technologies and biosensors.
Advances, Challenges and Future Trends of Cell-Free Transcription-Translation Biosensors
Authors: Wang Ting , Lu Yuan
Published: May 2022

In recent years, the application of cell-free protein synthesis systems in biosensing has been developing rapidly. Cell-free synthetic biology, with its advantages of high biosafety, fast material transport, and high sensitivity, has overcome many defects of cell-based biosensors and provided an abiotic substitute for biosensors. In addition, the application of freeze-drying technology has improved the stability of such systems, making it possible to realize point-of-care application of field detection and broadening the application prospects of cell-free biosensors. However, despite these advancements, challenges such as the risk of sample interference due to the lack of physical barriers, maintenance of activity during storage, and poor robustness still need to be addressed before the full potential of cell-free biosensors can be realized on a larger scale. In this review, current strategies and research results for improving the performance of cell-free biosensors are summarized, including a comprehensive discussion of the existing challenges, future trends, and potential investments needed for improvement.
Structural MRI-Based Schizophrenia Classification Using Autoencoders and 3D Convolutional Neural Networks in Combination with Various Pre-Processing Techniques
Authors: Vyškovský Roman , Schwarz Daniel , Churová Vendula , Kašpárek Tomáš
Published: May 2022

Schizophrenia is a severe neuropsychiatric disease whose diagnosis, unfortunately, lacks an objective diagnostic tool supporting a thorough psychiatric examination of the patient. We took advantage of today’s computational abilities, structural magnetic resonance imaging, and modern machine learning methods, such as stacked autoencoders (SAE) and 3D convolutional neural networks (3D CNN), to teach them to classify 52 patients with schizophrenia and 52 healthy controls. The main aim of this study was to explore whether complex feature extraction methods can help improve the accuracy of deep learning-based classifiers compared to minimally preprocessed data. Our experiments employed three commonly used preprocessing steps to extract three different feature types. They included voxel-based morphometry, deformation-based morphometry, and simple spatial normalization of brain tissue. In addition to classifier models, features and their combination, other model parameters such as network depth, number of neurons, number of convolutional filters, and input data size were also investigated. Autoencoders were trained on feature pools of 1000 and 5000 voxels selected by Mann-Whitney tests, and 3D CNNs were trained on whole images. The most successful model architecture (autoencoders) achieved the highest average accuracy of 69.62% (sensitivity 68.85%, specificity 70.38%). The results of all experiments were statistically compared (the Mann-Whitney test). In conclusion, SAE outperformed 3D CNN, while preprocessing using VBM helped SAE improve the results.
Dopamine Function and Hypothalamic-Pituitary-Thyroid Axis Activity in Major Depressed Patients with Suicidal Behavior
Authors: Duval Fabrice , Mokrani Marie-Claude , Danila Vlad , Erb Alexis , Gonzalez Lopera Felix , Tomsa Mihaela
Published: May 2022

Involvement of the dopaminergic (DA) and hypothalamic-pituitary-thyroid (HPT) systems in suicidal behavior is still poorly understood. We assessed multihormonal responses to apomorphine (APO; a short acting DA receptor agonist) and 8 AM and 11 PM protirelin (TRH) tests in 30 medication-free DSM-5 euthyroid major depressed inpatients with suicidal behavior disorder (SBD) (current, n = 14; in early remission, n = 16) and 18 healthy hospitalized control subjects (HCs). Compared to HCs, responses to APO and TRH tests were unaltered in SBDs in early remission. However, current SBDs exhibited increased APO-induced growth hormone (GH) and adrenocorticotropin (ACTH) stimulation, and reduced 11 PM thyrotropin (TSH) and ∆∆TSH values (difference between 11 PM and 8 AM TRH-TSH responses). In current SBDs, the association between high APO-GH concentrations and low ∆∆TSH values was more common in recent suicide attempters than in past suicide attempters. These preliminary results suggest that co-occurring alterations in the DA and HPT systems (i.e., DA receptor hyperresponsiveness associated with decreased hypothalamic TRH drive) may contribute to the pathophysiology of suicidal behavior. Conversely, normalization of DA and TRH functions might reflect a process of recovery from suicidality. Thus, our findings suggest that drugs targeting the DAergic and TRH systems could be relevant in suicide prevention.
Components of Active Music Interventions in Therapeutic Settings—Present and Future Applications
Authors: Schneider Lydia , Gossé Louisa , Montgomery Max , Wehmeier Moritz , Villringer Arno , Fritz Thomas Hans
Published: May 2022

Musical interventions in therapy have become increasingly relevant for rehabilitation in many clinics. What was long known for physiotherapy training—that the agency of the participant is crucial and moving is much more efficient for rehabilitation success than being moved—has over recent years also been shown to be true for music therapy. Accumulating evidence suggests that active musical interventions are especially efficient at helping rehabilitation success. Here, we review various approaches to active music therapy. Furthermore, we present several components that allow for manipulating musical expressiveness and physical engagement during active musical interventions, applying a technology-based music feedback paradigm. This paper will allow for a transfer of insights to other domains of music-based therapeutic interventions.
Review of Heliodon Developments and Computational Tools for Building Shadow Analysis
Authors: Salgado-Conrado Lizbeth , Lopez-Montelongo Areli , Alvarez-Macias Carlos , Hernadez-Jaquez Jose
Published: May 2022

In the last decade, the analysis of shading or sunlight in architectural projects has become an important role in improving building thermal and lighting performances. Selecting an appropriate software tool for this type of analysis is a challenging task given the little information available. Therefore, the paper reviews the existing literature on heliodon designs and computational tools for building shadow analysis. The review includes a detailed description and classification of various types of heliodons, along with their operating principles and geometric features that affect their performance, including light sources, positioning mechanisms, and structures. This paper also includes descriptions and classification of the computational tools for testing building shadow patterns and applications in architecture. Moreover, this paper shows the capabilities of different software packages and their essential features, strengths, and limitations. In addition, we identified the current gaps in the literature on heliodons and computational tools. According to the results, for the case of heliodons, there is a lack of error analysis and a standardized calibration process, therefore, repeatability of the results is difficult to achieve. In the case of computational tools, they have reached a higher degree of success in the market than the heliodons, however, the cost of licensing and learning curve can be a limitation.
Experimental Studies for Shear and Multi-Impact Resistance Performance of Sand–Geofoam Material
Authors: Ge Qi , Zuo Wenhao , Liu Renkuan , Zhu Baoying , Zhao Peng , Wan Li , Wang Yifan , Zhao Rong
Published: May 2022

In the case of earthquake and rockfall disasters, it is proposed to replace part of sand with geofoam material to form sand–EPS and sand–EPE composite cushions to improve the ability of structures to resist disasters. The shear performance of the sand–EPS beads mixture material with different moisture contents, the impact resistance of sand–EPS beads and sand–flocculent-EPE layered composite materials with different cushion thicknesses and different mass ratios were studied by direct shear tests and multi-impact tests. The results showed that with the increase in the moisture content, the shear strength of the sand–EPS beads decreased, the internal friction angle of sand–EPS decreased first and then increased, and the cohesion of sand–EPS increased first and then decreased. The sand–geofoam layered cushion had better buffering performance. Sand–EPE has better durability than Sand–EPS.
Precise Calibration of the Continuous Surface Cap Model for Concrete Simulation
Authors: Novozhilov Yury Vladislavovich , Dmitriev Andrey Nikolaevich , Mikhaluk Dmitry Sergeevich
Published: May 2022

The Continuous Surface Cap Model (CSCM) is one of the most widely used concrete models in LS-DYNA. The model is capable of capturing many important nonlinear mechanical behaviors of concrete well. The model has a built-in auto calibration procedure based on CEB-FIP code data. However, the built-in calibration procedure estimates material properties with significant errors, especially for tensile strength. Our study highlights the imperfection of the built-in automated material calibration procedure by the example of one-element uniaxial tension and compression tests. A calibration procedure is proposed, which significantly improves the accuracy of the material properties calculation: tensile and compressive strength and fracture energy. It is shown that the model with the proposed calibration procedure can describe the structure defamations and the fracture zone patterns more accurately.
Impact of Individual Comorbidities on Survival of Patients with Myelofibrosis
Authors: García-Fortes María , Hernández-Boluda Juan C. , Álvarez-Larrán Alberto , Raya José M. , Angona Anna , Estrada Natalia , Fox Laura , Cuevas Beatriz , García-Hernández María C. , Gómez-Casares María Teresa , Ferrer-Marín Francisca , Saavedra Silvana , Cervantes Francisco , García-Delgado Regina ,   on behalf of the Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas (GEMFIN)
Published: May 2022

The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.
Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer
Authors: Kakarla Mamatha , ChallaSivaKanaka Sathyavathi , Dufficy Mary F. , Gil Victoria , Filipovich Yana , Vickman Renee , Crawford Susan E. , Hayward Simon W. , Franco Omar E.
Published: May 2022

Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector cells. The consequences of continuous reverse Ephrin signaling activation in fibroblasts on prostate cancer (PCa) is unknown. When compared to benign prostate fibroblast, CAF displayed higher expression of Ephrin B1, B2, and B3 ligands (EFNB1, EFNB2, and EFNB3). In this study, we found that continuous activation of EFNB1 and EFNB3 in a benign human prostate stromal cell line (BHPrS1) increased the expression of CAF markers and induced a CAF phenotype. BHPrS1EFNB1 and BHPrS1EFNB3 displayed a pro-tumorigenic secretome with multiple effects on neovascularization, collagen deposition, and cancer cell proliferation, overall increasing tumorigenicity of a premalignant prostate epithelial cell line BPH1 and PCa cell line LNCaP, both in vitro and in vivo. Inhibition of Src family kinases (SFK) in BHPrS1EFNB1 and BHPrS1EFNB3 suppressed EFNB-induced ɑ-SMA (Alpha-smooth muscle actin) and TN-C (Tenascin-C) in vitro. Our study suggests that acquisition of CAF characteristics via SFK activation in response to increased EFNB ligands could promote carcinogenesis via modulation of TME in PCa.
Impact of Secretion-Active Osteoblast-Specific Factor 2 in Promoting Progression and Metastasis of Head and Neck Cancer
Authors: Gül Désirée , Schweitzer Andrea , Khamis Aya , Knauer Shirley K. , Ding Guo-Bin , Freudelsperger Laura , Karampinis Ioannis , Strieth Sebastian , Hagemann Jan , Stauber Roland H.
Published: May 2022

Treatment success of head and neck cancer (HNC) is still hampered by tumor relapse due to metastases. Our study aimed to identify biomarkers by exploiting transcriptomics profiles of patient-matched metastases, primary tumors, and normal tissue mucosa as well as the TCGA HNC cohort data sets. Analyses identified osteoblast-specific factor 2 (OSF-2) as significantly overexpressed in lymph node metastases and primary tumors compared to normal tissue. High OSF-2 levels correlate with metastatic disease and reduced overall survival of predominantly HPV-negative HNC patients. No significant correlation was observed with tumor localization or therapy response. These findings were supported by the fact that OSF-2 expression was not elevated in cisplatin-resistant HNC cell lines. OSF-2 was strongly expressed in tumor-associated fibroblasts, suggesting a tumor microenvironment-promoting function. Molecular cloning and expression studies of OSF-2 variants from patients identified an evolutionary conserved bona fide protein secretion signal (1MIPFLPMFSLLLLLIVNPINA21). OSF-2 enhanced cell migration and cellular survival under stress conditions, which could be mimicked by the extracellular administration of recombinant protein. Here, OSF-2 executes its functions via ß1 integrin, resulting in the phosphorylation of PI3K and activation of the Akt/PKB signaling pathway. Collectively, we suggest OSF-2 as a potential prognostic biomarker and drug target, promoting metastases by supporting the tumor microenvironment and lymph node metastases survival rather than by enhancing primary tumor proliferation or therapy resistance.
Oncopeptide MBOP Encoded by LINC01234 Promotes Colorectal Cancer through MAPK Signaling Pathway
Authors: Tang Chunyuan , Zhou Ying , Sun Wen , Hu Haihong , Liu Yuxi , Chen Lu , Ou Fengting , Zeng Su , Lin Nengming , Yu Lushan
Published: May 2022

Colorectal cancer (CRC) ranks third in incidence rate and second in mortality rate of malignancy worldwide, and the diagnosis and therapeutics of it remain to be further studied. With the emergence of noncoding RNAs (ncRNAs) and potential peptides derived from ncRNAs across various biological processes, we here aimed to identify a ncRNA-derived peptide possible for revealing the oncogenesis of CRC. Through combined predictive analysis of the coding potential of a batch of long noncoding RNAs (lncRNAs), the existence of an 85 amino-acid-peptide, named MEK1-binding oncopeptide (MBOP) and encoded from LINC01234 was confirmed. Mass spectrometry and Western blot assays indicated the overexpression of MBOP in CRC tissues and cell lines compared to adjacent noncancerous tissues and the normal colonic epithelial cell line. In vivo and in vitro migration and proliferation assays defined MBOP as an oncogenic peptide. Immunoprecipitation trials showed that MEK1 was the key interacting protein of MBOP, and MBOP promoted the MEK1/pERK/MMP2/MMP9 axis in CRC. Two E3-ligase enzymes MAEA and RMND5A mediated the ubiquitin–protease-system-related degradation of MBOP. This study indicates that MBOP might be a candidate prognostic indicator and a potential target for clinical therapy of CRC.
Azacitidine vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the PETHEMA Registry
Authors: Labrador Jorge , Martínez-Cuadrón David , de la Fuente Adolfo , Rodríguez-Veiga Rebeca , Serrano Josefina , Tormo Mar , Rodriguez-Arboli Eduardo , Ramos Fernando , Bernal Teresa , López-Pavía María , Trigo Fernanda , Martínez-Sánchez María Pilar , Rodríguez-Gutiérrez Juan-Ignacio , Rodríguez-Medina Carlos , Gil Cristina , Belmonte Daniel García , Vives Susana , Foncillas María-Ángeles , Pérez-Encinas Manuel , Novo Andrés , Recio Isabel , Rodríguez-Macías Gabriela , Bergua Juan Miguel , Noriega Víctor , Lavilla Esperanza , Roldán-Pérez Alicia , Sanz Miguel A. , Montesinos Pau ,   on behalf of PETHEMA Group
Published: May 2022

The hypomethylating agents, decitabine (DEC) and azacitidine (AZA), allowed more elderly acute myeloid leukemia (AML) patients to be treated. However, there are little direct comparative data on AZA and DEC. This multicenter retrospective study compared the outcomes of AZA and DEC in terms of response and overall survival (OS). Potential predictors associated with response and OS were also evaluated. A total of 626 AML patients were included (487 treated with AZA and 139 with DEC). Response rates were similar in both groups: CR was 18% with AZA vs. 23% with DEC (p = 0.20), CR/CRi was 20.5% vs. 25% (p = 0.27) and ORR was 32% vs. 39.5% (p = 0.12), respectively. Patients with leukocytes < 10 × 109/L, bone marrow blasts < 50% and ECOG ≥ 2 had higher ORR with DEC than with AZA. OS was similar in both groups: 10.4 months (95% CI: 9.2–11.7) vs. 8.8 months (95% CI: 6.7–11.0, p = 0.455), for AZA and DEC, respectively. Age (≥80 years), leukocytes (≥ 10 × 109/L), platelet count (<20 × 109/L) and eGFR (≥45 mL/min/1.73 m2) were associated with higher OS with AZA compared to DEC. In conclusion, we found no differences in response and OS rates in AML patients treated with AZA or DEC.
Calcium Channel Blocker Use and the Risk for Breast Cancer: A Population-Based Nested Case-Control Study
Authors: Rotshild Victoria , Hirsh Raccah Bruria , Gazawe Muna , Matok Ilan
Published: May 2022

We investigated whether long-term exposure to calcium channel blockers (CCBs) is associated with an increased risk of breast cancer (BCa). We designed a nested case–control study based on data from the Clalit electronic database, the largest Israeli Health Services organization. All newly diagnosed breast cancer (BCa) cases were selected from a cohort of patients with hypertension. Ten controls were matched for each BCa case. The odds ratios (ORs) of BCa among CCBs users were calculated using multivariate conditional logistic regression analyses. A total of 4875 patients with newly diagnosed BCa were identified from the cohort with a median follow-up of 5.15 years. The exposure to CCBs was not associated with an increased risk of BCa (OR = 0.98; 95% CI, 0.92–1.04). Additionally, there was no association between long-term exposure to CCBs (above eight years) and increased BCa risk (OR = 0.91; 95% CI, 0.67–1.21). Higher cumulative doses of CCBs were not associated with an elevated risk of BCa (OR = 0.997; 95% CI, 0.962–1.034, calculated per 1000 DDD). Based on this large population-based study, long-term exposure to CCBs was not associated with an increased risk of BCa. Considering that CCBs are widely used medications, our results provide important safety information on a population level, especially for patients with an increased risk of BCa.
Long-Term Survival, Prognostic Factors, and Quality of Life of Patients Undergoing Pelvic Exenteration for Cervical Cancer
Authors: Stanca Mihai , Căpîlna Dan Mihai , Căpîlna Mihai Emil
Published: May 2022

Background: Considerable efforts have been carried out over the past 30 years to support patients with advanced cervical cancer. Throughout this time, Eastern European countries have been left aside from the decision-making groups on this matter, hence the absence of similar studies in this geographical area. In these countries, the quality of life (QoL) of patients with cervical cancer might be considered a “caprice”, and the discomforts they encounter following pelvic exenteration for cervical cancer are often perceived as a “normal phenomenon”. Methods: This study examined forty-seven patients submitted to pelvic exenteration followed up for nine years after the surgical intervention. The first objective of this study is to identify the prognostic factors that influence the overall survival (OS) of patients undergoing pelvic exenteration for FIGO stage IVA, recurrent or persistent cervical cancer after previous conclusive treatments. The second objective is to assess the QoL of the surviving patients using the QLQ-C30 and QLQ-CX24 standardized questionnaires. Results: The mean age of the participants was 54 years (range 36–67). At the time of the study, there were 25 living patients (53.2%), the 3-year OS was 61%, and the 5-year OS was 48.7%. Cox regression analysis recognized parameter invasion, pelvic lymph node metastases, positive resection margins, early postoperative complications, and infralevatorian pelvic exenteration as negative prognostic factors influencing the OS (p < 0.05). Of the 25 survivors, 18 patients answered the QoL questionnaires. The cost of favorable survival has been translated into poor overall QoL, unsatisfactory functional, social, and symptom scores, a high prevalence of cervical cancer-specific symptoms such as lymphedema, peripheral neuropathy, severe menopausal symptoms, distorted body image, and lack of sexual desire. The lower scores are comparable to the only three studies available in the literature that assessed the QoL of patients undergoing pelvic exenteration precisely for cervical cancer. Conclusions: Despite its retrospective nature and some limitations, this paper, similar to other studies, shows a decent OS but with a marked adverse impact on QoL, suggesting the importance of adequate psycho-emotional and financial support for these patients following pelvic exenteration. This study also contributes to the current knowledge regarding advanced cervical cancer treatment, depicting survival, prognostic factors, and QoL of patients undergoing pelvic exenteration for cervical cancer in a reference center in Eastern Europe. Our study can provide a comparison for future prospective randomized trials needed to confirm these results.
Wide Next-Generation Sequencing Characterization of Young Adults Non-Small-Cell Lung Cancer Patients
Authors: Ulivi Paola , Urbini Milena , Petracci Elisabetta , Canale Matteo , Dubini Alessandra , Bartolini Daniela , Calistri Daniele , Cravero Paola , Fonzi Eugenio , Martinelli Giovanni , Priano Ilaria , Andrikou Kalliopi , Bronte Giuseppe , Crinò Lucio , Delmonte Angelo
Published: May 2022

Molecular characterization of advanced non-small-cell lung cancer (NSCLC) is mandatory before any treatment decision making. Next-generation sequencing (NGS) approaches represent the best strategy in this context. The turnaround time for NGS methodologies and the related costs are becoming more and more adaptable for their use in clinical practice. In our study, we analyzed a case series of young (under 65 years old) NSCLC patients with a wide NGS gene panel assay. The most frequent altered genes were TP53 (64.55%), followed by KRAS (44.1%), STK11 (26.9%), CDKN2A (21.5%), CDKN2B (14.0%), EGFR (16.1%), and RB1 (10.8%). Tumor mutational burden (TMB) was also evaluated. Considering the cut-off of 10 mut/Mb, 62 (68.9%) patients showed a TMB < 10 mut/Mb, whereas 28 (31.1%) showed a TMB ≥ 10 mut/Mb. STK11 and KRAS mutations were significantly associated with a higher TMB (p = 0.019 and p = 0.004, respectively). Conversely, EGFR and EML4-ALK alterations were more frequently found in tumors with low TMB (p = 0.019 and p < 0.001, respectively). We compared results obtained from this approach with those obtained from a single or few genes approach, observing perfect concordance of the results.
Genetic Screening of a Large Panel of Genes Associated with Cardiac Disease in a Spanish Heart Transplanted Cohort
Authors: Cuesta-Llavona Elías , Lorca Rebeca , Díaz-Molina Beatriz , Lambert-Rodríguez José L. , Reguero Julián R. , Iglesias Sara , Alonso Belén , Junco-Vicente Alejandro , Alonso Vanesa , Coto Eliecer , Gómez Juan
Published: May 2022

In this study we performed a next generation sequencing of 210 genes in 140 patients with cardiac failure requiring a heart transplantation. We identified a total of 48 candidate variants in 47 patients. Forty-three patients (90%) presented a single variant, and fourpatients (10%) were carriers of two variants. After refining the classification, we identified a pathogenic or likely pathogenic variant in 13 patients (10% of our cohort). In 34 additional cases (25%) the variants were classified as of unknown significance (VUS). In reference to the cause of cardiac failure in the 13 carriers of pathogenic variants, 5 were of dilated non-ischemic cause, 4 hypertrophic and 1 restrictive cardiomyopathy. In the ischemic cases (n = 3) no family history of cardiac disease was recorded, while nineof the non-ischemic had other relatives who were also diagnosed. In conclusion, the NGS of a cardiac transplanted cohort identified a definite or very likely genetic cause in 10% of the cases. Most of them had a family history of cardiac disease, and were thus previously studied as part of a routine screening by a genetic counselor. Pathogenic variants in cases without a family history of cardiac disease were mainly of ischemic origin.
Reduced Graphene Oxide Supported Zinc Tungstate Nanoparticles as Proficient Electro-Catalysts for Hydrogen Evolution Reactions
Authors: Alhokbany Norah , Ahamad Tansir , Alshehri Saad M. , Ahmed Jahangeer
Published: May 2022

The nanocomposites of reduced graphene oxide (rGO) supported zinc tungstate nanoparticles (ZnWO4-NPs) receive considerable attention in electro-catalytic hydrogen evolution reactions (HER) and reveal significantly higher electro-catalytic performances than pure ZnWO4-NPs in alkaline media (i.e., 0.5 M KOH electrolyte). The polarization studies show that the ZnWO4-NPs@rGO nanocomposites exhibit low energy loss and good electrode stability during electrochemical reactions for HER. Furthermore, the Tafel slope of ZnWO4-NPs@rGO nanocomposites is found to be approximately 149 mV/dec, which closely agrees with the reported Tafel values of the noble metal electrocatalyst. In contrast, the performance of the ZnWO4-NPs@rGO nanocomposite is found to be approximately 1.5 times higher than that of ZnWO4-NPs in hydrogen production efficiency. Our results emphasize the significance of the nanocomposites with enhanced electro-catalytic activities by lowering the energy loss during electro-catalysis in an alkaline medium.
One-Pot Synthesis of Benzopyrano-Pyrimidine Derivatives Catalyzed by P-Toluene Sulphonic Acid and Their Nematicidal and Molecular Docking Study
Authors: Parveen Mehtab , Azeem Mohammad , Khan Azmat Ali , Aslam Afroz , Fatima Saba , Siddiqui Mansoor A. , Azim Yasser , Min Kim , Alam Mahboob
Published: May 2022

A cost-effective and environmentally benign benzopyrano-pyrimidine derivative synthesis has been established with the condensation of different salicylaldehyde derivatives, piperidine/morpholine with malononitrile, in the presence of a catalyst containing p-toluene sulphonic acid (PTSA) at 80 °C temperature. This procedure offers a new and enriched approach for synthesizing benzopyrano-pyrimidine derivatives with high yields, a straightforward experimental method, and short reaction times. The synthesized compounds were investigated for their nematocidal activity, and the result shows that among the four compounds, compounds 4 and 5 showed strong nematocidal activity against egg hatching and J2s mortality. The nematocidal efficacy of the compounds might be due to the toxicity of chemicals which are soluble in ethanol. The nematocidal effectiveness was directly related to the concentration of ethanolic dilutions of the compounds, i.e., the maximum treatment concentration, the higher the nematocidal action, or the higher the mortality and egg hatching inhibition. In the present study, with support from docking analysis, the relation between chemical reactivity and nematocidal activity of compound 4 was inferred.
Surface Hydration Protects Cystic Fibrosis Airways from Infection by Restoring Junctional Networks
Authors: Simonin Juliette L. , Luscher Alexandre , Losa Davide , Badaoui Mehdi , van Delden Christian , Köhler Thilo , Chanson Marc
Published: May 2022

Defective hydration of airway surface mucosa is associated with recurrent lung infection in cystic fibrosis (CF), a disease caused by CF transmembrane conductance regulator (CFTR) gene mutations. Whether the composition and/or presence of an airway surface liquid (ASL) is sufficient to prevent infection remains unclear. The susceptibility to infection of polarized wild type and CFTR knockdown (CFTR-KD) airway epithelial cells was determined in the presence or absence of a healthy ASL or physiological saline. CFTR-KD epithelia exhibited strong ASL volume reduction, enhanced susceptibility to infection, and reduced junctional integrity. Interestingly, the presence of an apical physiological saline alleviated disruption of the airway epithelial barrier by stimulating essential junctional protein expression. Thus, rehydrated CFTR-KD cells were protected from infection despite normally intense bacterial growth. This study indicates that an epithelial integrity gatekeeper is modulated by the presence of an apical liquid volume, irrespective of the liquid’s composition and of expression of a functional CFTR.
Defining the Skeletal Myogenic Lineage in Human Pluripotent Stem Cell-Derived Teratomas
Authors: Pappas Matthew P. , Xie Ning , Penaloza Jacqueline S. , Chan Sunny S. K.
Published: May 2022

Skeletal muscle stem cells are essential to muscle homeostasis and regeneration after injury, and have emerged as a promising cell source for treating skeletal disorders. An attractive approach to obtain these cells utilizes differentiation of pluripotent stem cells (PSCs). We recently reported that teratomas derived from mouse PSCs are a rich source of skeletal muscle stem cells. Here, we showed that teratoma formation is also capable of producing skeletal myogenic progenitors from human PSCs. Using single-cell transcriptomics, we discovered several distinct skeletal myogenic subpopulations that represent progressive developmental stages of the skeletal myogenic lineage and recapitulate human embryonic skeletal myogenesis. We further discovered that ERBB3 and CD82 are effective surface markers for prospective isolation of the skeletal myogenic lineage in human PSC-derived teratomas. Therefore, teratoma formation provides an accessible model for obtaining human skeletal myogenic progenitors from PSCs.
The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling
Authors: Mancinelli Romina , Ceci Ludovica , Kennedy Lindsey , Francis Heather , Meadows Vik , Chen Lixian , Carpino Guido , Kyritsi Konstantina , Wu Nan , Zhou Tianhao , Sato Keisaku , Pannarale Luigi , Glaser Shannon , Chakraborty Sanjukta , Alpini Gianfranco , Gaudio Eugenio , Onori Paolo , Franchitto Antonio
Published: May 2022

Background & aims: Cholangiocytes are the target cells of liver diseases that are characterized by biliary senescence (evidenced by enhanced levels of senescence-associated secretory phenotype, SASP, e.g., TGF-β1), and liver inflammation and fibrosis accompanied by altered bile acid (BA) homeostasis. Taurocholic acid (TC) stimulates biliary hyperplasia by activation of 3′,5′-cyclic cyclic adenosine monophosphate (cAMP) signaling, thereby preventing biliary damage (caused by cholinergic/adrenergic denervation) through enhanced liver angiogenesis. Also: (i) α-calcitonin gene-related peptide (α-CGRP, which activates the calcitonin receptor-like receptor, CRLR), stimulates biliary proliferation/senescence and liver fibrosis by enhanced biliary secretion of SASPs; and (ii) knock-out of α-CGRP reduces these phenotypes by decreased cAMP levels in cholestatic models. We aimed to demonstrate that TC effects on liver phenotypes are dependent on changes in the α-CGRP/CALCRL/cAMP/PKA/ERK1/2/TGF-β1/VEGF axis. Methods: Wild-type and α-CGRP−/− mice were fed with a control (BAC) or TC diet for 1 or 2 wk. We measured: (i) CGRP levels by both ELISA kits in serum and by qPCR in isolated cholangiocytes (CALCA gene for α-CGRP); (ii) CALCRL immunoreactivity by immunohistochemistry (IHC) in liver sections; (iii) liver histology, intrahepatic biliary mass, biliary senescence (by β-GAL staining and double immunofluorescence (IF) for p16/CK19), and liver fibrosis (by Red Sirius staining and double IF for collagen/CK19 in liver sections), as well as by qPCR for senescence markers in isolated cholangiocytes; and (iv) phosphorylation of PKA/ERK1/2, immunoreactivity of TGF-β1/TGF- βRI and angiogenic factors by IHC/immunofluorescence in liver sections and qPCR in isolated cholangiocytes. We measured changes in BA composition in total liver by liquid chromatography/mass spectrometry. Results: TC feeding increased CALCA expression, biliary damage, and liver inflammation and fibrosis, as well as phenotypes that were associated with enhanced immunoreactivity of the PKA/ERK1/2/TGF-β1/TGF-βRI/VEGF axis compared to BAC-fed mice and phenotypes that were reversed in α-CGRP−/− mice fed TC coupled with changes in hepatic BA composition. Conclusion: Modulation of the TC/ α-CGRP/CALCRL/PKA/ERK1/2/TGF-β1/VEGF axis may be important in the management of cholangiopathies characterized by BA accumulation.
Determination of Ascorbic Acid in Pharmaceuticals and Food Supplements with the New Potassium Ferrocyanide-Doped Polypyrrole-Modified Platinum Electrode Sensor
Authors: Dinu Ancuța , Apetrei Constantin
Published: May 2022

This paper reports the results obtained from the determination of ascorbic acid with platinum-based voltammetric sensors modified with potassium hexacyanoferrate-doped polypyrrole. The preparation of the modified electrodes was carried out by electrochemical polymerization of pyrrole from aqueous solutions, using chronoamperometry. Polypyrrole films were deposited on the surface of the platinum electrode, by applying a constant potential of 0.8 V for 30 s. The thickness of the polymer film was calculated from the chronoamperometric data, and the value was 0.163 μm. Cyclic voltammetry was the method used for the Pt/PPy-FeCN electrode electrochemical characterization in several types of solution, including KCl, potassium ferrocyanide, and ascorbic acid. The thin doped polymer layer showed excellent sensitivity for ascorbic acid detection. From the voltammetric studies carried out in solutions of different concentrations of ascorbic acid, ranging from 1 to 100 × 10−6 M, a detection limit of 2.5 × 10−7 M was obtained. Validation of the analyses was performed using pharmaceutical products with different concentrations of ascorbic acid, from different manufacturers and presented in various pharmaceutical forms, i.e., intravascular administration ampoules, chewable tablets, and powder for oral suspension.
Couplants in Acoustic Biosensing Systems
Authors: Manwar Rayyan , Saint-Martin Loїc , Avanaki Kamran
Published: May 2022

Acoustic biosensors are widely used in physical, chemical, and biosensing applications. One of the major concerns in acoustic biosensing is the delicacy of the medium through which acoustic waves propagate and reach acoustic sensors. Even a small airgap diminishes acoustic signal strengths due to high acoustic impedance mismatch. Therefore, the presence of a coupling medium to create a pathway for an efficient propagation of acoustic waves is essential. Here, we have reviewed the chemical, physical, and acoustic characteristics of various coupling material (liquid, gel-based, semi-dry, and dry) and present a guide to determine a suitable application-specific coupling medium.