bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Study: Intra- and Interpersonal Coherence of Muscle and Brain Activity of Two Coupled Persons during Pushing and Holding Isometric Muscle Action
Authors: Schaefer Laura V. , Bittmann Frank N.
Published: May 2022

Inter-brain synchronization is primarily investigated during social interactions but had not been examined during coupled muscle action between two persons until now. It was previously shown that mechanical muscle oscillations can develop coherent behavior between two isometrically interacting persons. This case study investigated if inter-brain synchronization appears thereby, and if differences of inter- and intrapersonal muscle and brain coherence exist regarding two different types of isometric muscle action. Electroencephalography (EEG) and mechanomyography/mechanotendography (MMG/MTG) of right elbow extensors were recorded during six fatiguing trials of two coupled isometrically interacting participants (70% MVIC). One partner performed holding and one pushing isometric muscle action (HIMA/PIMA; tasks changed). The wavelet coherence of all signals (EEG, MMG/MTG, force, ACC) were analyzed intra- and interpersonally. The five longest coherence patches in 8–15 Hz and their weighted frequency were compared between real vs. random pairs and between HIMA vs. PIMA. Real vs. random pairs showed significantly higher coherence for intra-muscle, intra-brain, and inter-muscle-brain activity (p < 0.001 to 0.019). Inter-brain coherence was significantly higher for real vs. random pairs for EEG of right and central areas and for sub-regions of EEG left (p = 0.002 to 0.025). Interpersonal muscle-brain synchronization was significantly higher than intrapersonal one, whereby it was significantly higher for HIMA vs. PIMA. These preliminary findings indicate that inter-brain synchronization can arise during muscular interaction. It is hypothesized both partners merge into one oscillating neuromuscular system. The results reinforce the hypothesis that HIMA is characterized by more complex control strategies than PIMA. The pilot study suggests investigating the topic further to verify these results on a larger sample size. Findings could contribute to the basic understanding of motor control and is relevant for functional diagnostics such as the manual muscle test which is applied in several disciplines, e.g., neurology, physiotherapy.
The Impact of Chronic Unpredictable Mild Stress-Induced Depression on Spatial, Recognition and Reference Memory Tasks in Mice: Behavioral and Histological Study
Authors: Alqurashi Ghofran Khalid , Hindi Emad A. , Zayed Mohamed A. , Abd El-Aziz Gamal S. , Alturkistani Hani A. , Ibrahim Rabee F. , Al-thepyani Mona Ali , Bakhlgi Refal , Alzahrani Noor A. , Ashraf Ghulam Md , Alghamdi Badrah S.
Published: May 2022

Depression-induced cognitive impairment has recently been given more attention in research. However, the relationship between depression and different types of memory is still not clear. Chronic unpredictable mild stress (CUMS) is a commonly used animal model of depression in which animals are exposed to chronic unpredictable environmental and psychological stressors, which mimics daily human life stressors. This study investigated the impact of different durations of CUMS on various types of memory (short- and long-term spatial memory and recognition memory) and investigated CUMS’ impact on the ultrastructural level by histological assessment of the hippocampus and prefrontal cortex. Twenty male C57BL/J6 mice (6 weeks old, 21.8 ± 2 g) were randomly divided into two groups (n = 10): control and CUMS (8 weeks). A series of behavioral tasks were conducted twice at weeks 5–6 (early CUMS) and weeks 7–8 (late CUMS). A tail-suspension test (TST), forced swimming test (FST), elevated zero maze (EZM), elevated plus maze (EPM), open field test (OFT), and sucrose-preference test (SPT) were used to assess anxiety and depressive symptoms. The cognitive function was assessed by the novel object recognition test (NORT; for recognition memory), Y-maze (for short-term spatial memory), and Morris water maze (MWM: for long-term spatial memory) with a probe test (for reference memory). Our data showed that 8 weeks of CUMS increased the anxiety level, reported by a significant increase in anxiety index in both EPM and EZM and a significant decrease in central preference in OFT, and depression was reported by a significant increase in immobility in the TST and FST and sucrose preference in the SPT. Investigating the impact of CUMS on various types of memory, we found that reference memory is the first memory to be affected in early CUMS. In late CUMS, all types of memory were impaired, and this was consistent with the abnormal histological features of the memory-related areas in the brain (hippocampus and prefrontal cortex).
Vibration Serviceability Assessment of a Historic Suspension Footbridge
Authors: Bayat Elyas , Milone Angelo , Tubino Federica , Venuti Fiammetta
Published: May 2022

Experimental and numerical studies for the structural and vibration serviceability assessment of a historic suspension footbridge adopting non-invasive surveys and low-cost equipment are presented. Field surveys have been carried out to determine geometric properties, ambient vibration tests have been performed to estimate the dynamic properties, and the dynamic response of the footbridge under the action of a single crossing pedestrian has been recorded. Based on field surveys, a 3D Finite Element model was built and was then calibrated against ambient vibration test results. The experimentally-measured maximum acceleration under the action of one crossing pedestrian is compared with the ones obtained numerically and analytically. Furthermore, vibration serviceability assessment under multi-pedestrian loading is carried out, adopting the simplified procedure recommended by a recent guideline. Results show that low-cost non-invasive dynamic testing is suitable to correctly identify the footbridge vertical natural frequencies and mode shapes, including higher-order ones, and to draw considerations about the state of degradation of the structure. Moreover, the level of vibration under the action of a single pedestrian can be estimated with sufficient accuracy using a simplified loading model, provided that the modal damping ratio is properly tuned.
A Maturity Model for Resilient Safety Culture Development in Construction Companies
Authors: Trinh Minh Tri , Feng Yingbin
Published: May 2022

A resilient safety culture is characterized by the capability of addressing the changing and unforeseen safety risks associated with the increasingly complex nature of sociotechnical systems, and creating an ultrasafe organization. An assessment of the maturation of resilient safety culture helps organizations to evaluate their capabilities of managing safety risks and achieving a consistently high safety performance. This study aims to present a maturity model developed to measure and improve resilient safety culture in the construction environment. The research was conducted in two stages. The first stage consisted of a review of the literature on the concepts of a resilient safety culture and the capability maturity model for the development of a maturity model. In the second stage, the developed model was evaluated using the Delphi technique. The model defines five maturity levels that can be used to measure resilient safety culture of a construction organization. It presents a set of descriptions of 19 aspects of resilient safety culture at each maturity level. The assessment procedure and the way of using the model are further discussed. Theoretically, this study provides insights into the maturity characteristics of a resilient safety culture. In practical terms, it offers guidance for benchmarking and encouraging the enhancement of organizations’ capabilities to manage safety risks.
Interpretation of Machine-Learning-Based (Black-box) Wind Pressure Predictions for Low-Rise Gable-Roofed Buildings Using Shapley Additive Explanations (SHAP)
Authors: Meddage Pasindu , Ekanayake Imesh , Perera Udara Sachinthana , Azamathulla Hazi Md. , Md Said Md Azlin , Rathnayake Upaka
Published: May 2022

Conventional methods of estimating pressure coefficients of buildings retain time and cost constraints. Recently, machine learning (ML) has been successfully established to predict wind pressure coefficients. However, regardless of the accuracy, ML models are incompetent in providing end-users’ confidence as a result of the black-box nature of predictions. In this study, we employed tree-based regression models (Decision Tree, XGBoost, Extra-tree, LightGBM) to predict surface-averaged mean pressure coefficient (Cp,mean), fluctuation pressure coefficient (Cp,rms), and peak pressure coefficient (Cp,peak) of low-rise gable-roofed buildings. The accuracy of models was verified using Tokyo Polytechnic University (TPU) wind tunnel data. Subsequently, we used Shapley Additive Explanations (SHAP) to explain the black-box nature of the ML predictions. The comparison revealed that tree-based models are efficient and accurate in wind-predicting pressure coefficients. Interestingly, SHAP provided human-comprehensible explanations for the interaction of variables, the importance of features towards the outcome, and the underlying reasoning behind the predictions. Moreover, SHAP confirmed that tree-based predictions adhere to the flow physics of wind engineering, advancing the fidelity of ML-based predictions.
Nanomedicine for the Delivery of RNA in Cancer
Authors: Ghidini Michele , Silva Sandra G. , Evangelista Jessica , do Vale Maria Luísa C. , Farooqi Ammad Ahmad , Pinheiro Marina
Published: May 2022

The complexity, and the diversity of the different types of cancers allied to the tendency to form metastasis make treatment efficiency so tricky and often impossible due to the advanced stage of the disease in the diagnosis. In recent years, due to tremendous scientific breakthroughs, we have witnessed exponential growth in the elucidation of mechanisms that underlie carcinogenesis and metastasis. The development of more selective therapies made it possible to improve cancer treatment. Although interdisciplinary research leads to encouraging results, scientists still have a long exploration journey. RNA technology represents a promise as a therapeutic intervention for targeted gene silencing in cancer, and there are already some RNA-based formulations in clinical trials. However, the use of RNA as a therapeutic tool presents severe limitations, mainly related to its low stability and poor cellular uptake. Thus, the use of nanomedicine employing nanoparticles to encapsulate RNA may represent a suitable platform to address the major challenges hampering its therapeutic application. In this review, we have revisited the potential of RNA and RNA-associated therapies to fight cancer, also providing, as support, a general overview of nanoplatforms for RNA delivery.
A Patient Selection Approach Based on NTCP Models and DVH Parameters for Definitive Proton Therapy in Locally Advanced Sinonasal Cancer Patients
Authors: Mirandola Alfredo , Russo Stefania , Bonora Maria , Vischioni Barbara , Camarda Anna Maria , Ingargiola Rossana , Molinelli Silvia , Ronchi Sara , Rossi Eleonora , Vai Alessandro , Iacovelli Nicola Alessandro , Thariat Juliette , Ciocca Mario , Orlandi Ester
Published: May 2022

(1) Background: In this work, we aim to provide selection criteria based on normal tissue complication probability (NTCP) models and additional explanatory dose-volume histogram parameters suitable for identifying locally advanced sinonasal cancer patients with orbital invasion benefitting from proton therapy. (2) Methods: Twenty-two patients were enrolled, and two advanced radiation techniques were compared: intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT). Plans were optimized with a simultaneous integrated boost modality: 70 and 56 Gy(RBE) in 35 fractions were prescribed to the high risk/low risk CTV. Several endpoints were investigated, classified for their severity and used as discriminating paradigms. In particular, when NTCP models were already available, a first selection criterion based on the delta-NTCP was adopted. Additionally, an overall analysis in terms of DVH parameters was performed. Furthermore, a second selection criterion based on a weighted sum of the ΔNTCP and ΔDVH was adopted. (3) Results: Four patients out of 22 (18.2%) were suitable for IMPT due to ΔNTCP > 3% for at least one severe toxicity, 4 (18.2%) due to ΔNTCP > 20% for at least three concurrent intermediate toxicities and 16 (72.7%) due to the mixed sum of ΔNTCP and ΔDVH criterion. Since, for some cases, both criteria were contemporary fulfilled, globally 17/22 patients (77.3%) would benefit from IMPT. (4) Conclusions: For this rare clinical scenario, the use of a strategy including DVH parameters and NTCPs when comparing VMAT and IMPT is feasible. We showed that patients affected by sinonasal cancer could profit from IMPT compared to VMAT in terms of optical and central nervous system organs at risk sparing.
Expression Profile and Diagnostic Significance of MicroRNAs in Papillary Thyroid Cancer
Authors: Rogucki Mariusz , Sidorkiewicz Iwona , Niemira Magdalena , Dzięcioł Janusz Bogdan , Buczyńska Angelika , Adamska Agnieszka , Siewko Katarzyna , Kościuszko Maria , Maliszewska Katarzyna , Wójcicka Anna , Supronik Jakub , Szelachowska Małgorzata , Reszeć Joanna , Krętowski Adam Jacek , Popławska-Kita Anna
Published: May 2022

The incidence of papillary thyroid cancer (PTC) has increased in recent years. To improve the diagnostic management of PTC, we propose the use of microRNAs (miRNAs) as a biomarker. Our aim in this study was to evaluate the miRNA expression pattern in PTC using NanoString technology. We identified ten miRNAs deregulated in PTC compared with reference tissue: miR-146b-5p, miR-221-3p, miR-221-5p, miR-34-5p, miR-551b-3p, miR-152-3p, miR-15a-5p, miR-31-5p, and miR-7-5p (FDR < 0.05; |fold change (FC)| ≥ 1.5). The gene ontology (GO) analysis of differentially expressed miRNA (DEM) target genes identified the predominant involvement of epidermal growth factor receptor (EGFR), tyrosine kinase inhibitor resistance, and pathways in cancer in PTC. The highest area under the receiver operating characteristic (ROC) curve (AUC) for DEMs was found for miR-146-5p (AUC = 0.770) expression, indicating possible clinical applicability in PTC diagnosis. The combination of four miRNAs (miR-152-3p, miR-221-3p, miR-551b-3p, and miR-7-5p) showed an AUC of 0.841. Validation by real-time quantitative polymerase chain reactions (qRT-PCRs) confirmed our findings. The introduction of an miRNA diagnostic panel based on the results of our study may help to improve therapeutic decision making for questionable cases. The use of miRNAs as biomarkers of PTC may become an aspect of personalized medicine.
Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia
Authors: Piktel Debbie , Nair Rajesh R. , Rellick Stephanie L. , Geldenhuys Werner J. , Martin Karen H. , Craig Michael D. , Gibson Laura F.
Published: May 2022

The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown to be active in acute myeloid leukemia, prompting us to evaluate it in our in vitro co-culture model, which supports a chemo-resistant ALL population. We used phospho-protein profiling to evaluate the use of lipid metabolic active compounds in these chemo-resistant cells, due to the up-regulation of multiple active survival signals. In a co-culture with stromal cells, a shift towards anabolic processes occurred, which was further confirmed by assays showing increased lipid content. The treatment of REH leukemia cells with pitavastatin in the co-culture model resulted in significantly higher leukemic cell death than exposure to the standard-of-care chemotherapeutic agent, cytarabine (Ara-C). Our data demonstrates the use of pitavastatin as a possible alternative treatment strategy to improve patient outcomes in chemo-resistant, relapsed ALL.
Are Postoperative Infections in the First 12 Months after Wide Resection and Megaprosthetic Replacement Associated with the Survival of Osteosarcoma Patients? Results of a Multicenter Study
Authors: Schwering Christine , Niethard Maya , Gosheger Georg , Smolle Maria , Traub Frank , Adam Simon , Henrichs Marcel-Philipp , Dürr Hans , Hardes Jendrik , Tunn Per-Ulf , Leithner Andreas , Andreou Dimosthenis
Published: May 2022

Recent retrospective studies suggested that early postoperative infections might be associated with a survival benefit for extremity osteosarcoma patients, but the reported results have been conflicting. The files of 437 patients with a newly diagnosed, high-grade osteosarcoma of the extremities treated at 5 referral centers in Germany and Austria between 1989 and 2016 were retrospectively evaluated. All patients underwent multi-agent chemotherapy and limb-sparing tumor excision, followed by endoprothetic replacement. We used the Kaplan–Meier method to calculate survival curves, which we compared with the log-rank test. With a median follow-up of 100 months (interquartile range, 49–155 months), local recurrence (LR) probability, event-free survival (EFS), and disease-specific survival (DSS) after 5 years in this selected patient cohort amounted to 5%, 67%, and 79%, respectively, and 46 patients (10.5%) developed an early postoperative infection. We found no significant differences in LR, EFS, or DSS between patients with and without early infections, and there were no differences in known prognostic factors between the two groups. However, in subgroup analyses patients with a poor response to neoadjuvant chemotherapy and an early infection had a better DSS compared to patients without early infections (93% vs. 62% after 5 years, p = 0.044). Provided that our findings can be validated in separate patient cohorts, we believe that patient outcome after adjuvant immunomodulatory treatments in osteosarcoma patients should be evaluated and reported separately for good and poor responders to neoadjuvant chemotherapy in future studies.
The Clinical Applications of Liquid Biopsies in Pediatric Brain Tumors: A Systematic Literature Review
Authors: Greuter Ladina , Frank Nicole , Guzman Raphael , Soleman Jehuda
Published: May 2022

Background: Pediatric brain tumors are the most common solid tumor in children. Traditionally, tumor diagnosis and molecular analysis were carried out on tumor tissue harvested either via biopsy or resection. However, liquid biopsy allows analysis of circulating tumor DNA in corporeal fluids such as cerebrospinal fluid or blood. Methods: We performed a systematic review in Pubmed and Embase regarding the role of liquid biopsy in pediatric brain tumors. Results: Nine studies with a total of 570 patients were included. The preferred corporeal fluid for analysis with a relatively high yield of ct-DNA was cerebrospinal fluid (CSF). For high-grade glioma, liquid biopsy can successfully characterize H3K27mutations and predict tumor progression before it is radiographically detected. Moreover, liquid biopsy has the potential to distinguish between pseudo-progression and actual progression. In medulloblastoma, ct-DNA in the CSF can be used as a surrogate marker of measurable residual disease and correlates with response to therapy and progression of the tumor up to three months before radiographic detection. Conclusion: Liquid biopsy is primarily useful in high-grade pediatric brain tumors such as diffuse midline glioma or medulloblastoma. Disease detection and monitoring is feasible for both tumor entities. More trials to standardize its use for pediatric brain tumors are necessary.
Pancreatic Cancer and Microenvironments: Implications of Anesthesia
Authors: Lai Hou-Chuan , Kuo Yi-Wei , Huang Yi-Hsuan , Chan Shun-Ming , Cheng Kuang-I , Wu Zhi-Fu
Published: May 2022

Pancreatic malignancy is a lethal neoplasm, as well as one of the leading causes of cancer-associated mortality, having a 5-year overall survival rate of less than 10%. The average life expectancy of patients with advanced pancreatic cancer does not exceed six months. Although surgical excision is a favorable modality for long-term survival of pancreatic neoplasm, metastasis is initially identified in nearly 80% of the patients by the time of diagnosis, making the development of therapeutic policy for pancreatic cancer extremely daunting. Emerging evidence shows that pancreatic neoplastic cells interact intimately with a complicated microenvironment that can foster drug resistance, metastasis, or relapse in pancreatic cancer. As a result, the necessity of gaining further insight should be focused on the pancreatic microenvironment contributing to cancer progression. Numerous evidence reveals that perioperative factors, including surgical manipulation and anesthetics (e.g., propofol, volatile anesthetics, local anesthetics, epidural anesthesia/analgesia, midazolam), analgesics (e.g., opioids, non-steroidal anti-inflammatory drugs, tramadol), and anesthetic adjuvants (such as ketamine and dexmedetomidine), might alter the tumor microenvironment and cancer progression by affecting perioperative inflammatory or immune responses during cancer surgery. Therefore, the anesthesiologist plays an important role in perioperative management and may affect surgical outcomes. However, the literature on the impact of anesthesia on the pancreatic cancer microenvironment and progression is limited. This review summarizes the current knowledge of the implications of anesthesia in the pancreatic microenvironment and provides future anesthetic strategies for improving pancreatic cancer survival rates.
New Therapy Options for Neuroendocrine Carcinoma of the Pancreas—The Emergent Substance GP-2250 and Gemcitabine Prove to Be Highly Effective without the Development of Secondary Resistances In Vitro and In Vivo
Authors: Buchholz Marie , Strotmann Johanna , Majchrzak-Stiller Britta , Hahn Stephan , Peters Ilka , Horn Julian , Müller Thomas , Höhn Philipp , Uhl Waldemar , Braumann Chris
Published: May 2022

Neuroendocrine carcinoma of the pancreas (pNEC) is an aggressive form of neuroendocrine tumor characterized by a rising incidence without an increase in survival rates. GP-2250 is an oxathiazinane derivate possessing antineoplastic effects, especially in combination with Gemcitabine on the pancreatic adenocarcinoma. The cytotoxic effects of the monotherapy of GP-2250 (GP-2250mono) and Gemcitabine (Gemmono), as well as the combination therapy of both, were studied in vitro using an MTT-assay on the QGP-1 and BON-1 cell lines, along with in vivo studies on a murine xenograft model of QGP-1 and a patient-derived xenograft model (PDX) of Bo99. In vitro, Gemmono and GP-2250mono showed a dose-dependent cytotoxicity. The combination of GP-2250 and Gemcitabine exhibited highly synergistic effects. In vivo, the combination therapy obtained a partial response in QGP-1, while GP-2250mono and Gemmono showed progressive disease or stable disease, respectively. In Bo99 PDX, the combination therapy led to a partial response, while the monotherapy resulted in progressive disease. No development of secondary resistances was observed, as opposed to monotherapy. This study was the first to evaluate the effects of the emerging substance GP-2250 on pNEC. The substance showed synergism in combination with Gemcitabine. The combination therapy proved to be effective in vitro and in vivo, without the development of secondary resistances.
Significance of Specific Oxidoreductases in the Design of Hypoxia-Activated Prodrugs and Fluorescent Turn off–on Probes for Hypoxia Imaging
Authors: Janczy-Cempa Ewelina , Mazuryk Olga , Kania Agnieszka , Brindell Małgorzata
Published: May 2022

Hypoxia is one of the hallmarks of the tumor microenvironment and can be used in the design of targeted therapies. Cellular adaptation to hypoxic stress is regulated by hypoxia-inducible factor 1 (HIF-1). Hypoxia is responsible for the modification of cellular metabolism that can result in the development of more aggressive tumor phenotypes. Reduced oxygen concentration in hypoxic tumor cells leads to an increase in oxidoreductase activity that, in turn, leads to the activation of hypoxia-activated prodrugs (HAPs). The same conditions can convert a non-fluorescent compound into a fluorescent one (fluorescent turn off–on probes), and such probes can be designed to specifically image hypoxic cancer cells. This review focuses on the current knowledge about the expression and activity of oxidoreductases, which are relevant in the activation of HAPs and fluorescent imaging probes. The current clinical status of HAPs, their limitations, and ways to improve their efficacy are briefly discussed. The fluorescence probes triggered by reduction with specific oxidoreductase are briefly presented, with particular emphasis placed on those for which the correlation between the signal and enzyme expression determined with biochemical methods is achievable.
Clinical Presentation of Immune-Related Endocrine Adverse Events during Immune Checkpoint Inhibitor Treatment
Authors: Chieng Jenny Hui Ling , Htet Zaw Win , Zhao Joseph J. , Tai E Shyong , Tay Sen Hee , Huang Yiqing , Wong Alvin , Yang Samantha Peiling
Published: May 2022

The exact clinical course and factors associated with persistent endocrine immune-related adverse events (irAEs) are not well-established. Elucidation of these information will aid irAEs screening and follow-up planning for patients on immunotherapy. We analysed the clinical course of endocrine irAEs including thyroid and pituitary dysfunction and insulin-dependent diabetes mellitus (IDDM), identified factors associated with persistent thyroid dysfunction, and determined the association between endocrine irAEs and survival parameters. This retrospective observational study enrolled patients with metastatic cancer who underwent anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 treatment and developed endocrine irAE at the National University Cancer Institute, Singapore, between June 2015 and December 2020. Sixty-six patients with endocrine irAE were evaluated, with a median follow-up time of 15.7 months. The median time to onset of thyroid dysfunction, pituitary dysfunction, and IDDM was 1.8 months (range: 0.3–15.8 months), 6.8 months (range: 1.5–27.3 months), and 7.8 months (range: 1.4–9.1 months), respectively. Positive thyroperoxidase antibodies (TPOAb) and/ or thyroglobulin antibodies (TgAb) status at the time of thyroid dysfunction was associated with persistent thyroid dysfunction (OR 11.6, 95% CI 1.3–570.8, p = 0.02; OR 8.8, 95% CI 1.3–106.9, p = 0.01, respectively). All patients with pituitary irAE had central hypocortisolism. All patients with IDDM had grade 4 irAE. Patients with endocrine irAE had longer median survival times. Endocrine irAEs were associated with non-progressive disease. The screening and follow-up approach for endocrine irAEs should be tailored according to each endocrinopathy’s clinical course. Early screening is imperative given its wide median time to onset.
Stereotactic Ablative Radiotherapy Using CALYPSO® Extracranial Tracking for Intrafractional Tumor Motion Management—A New Potential Local Treatment for Unresectable Locally Advanced Pancreatic Cancer? Results from a Retrospective Study
Authors: Kaučić Hrvoje , Kosmina Domagoj , Schwarz Dragan , Mack Andreas , Šobat Hrvoje , Čehobašić Adlan , Leipold Vanda , Andrašek Iva , Avdičević Asmir , Mlinarić Mihaela
Published: May 2022

(1) Background: The aim of this study was to evaluate the efficacy and safety of SABR for LAPC using Calypso® Extracranial Tracking for intrafractional, fiducial-based motion management, to present this motion management technique, as there are yet no published data on usage of Calypso® during SABR for LAPC, and to report on our clinical outcomes. (2) Methods: Fifty-four patients were treated with SABR in one, three, or five fractions, receiving median BED10 = 112.5 Gy. Thirty-eight patients received systemic treatment. End points were OS, FFLP, PFS, and toxicity. Actuarial survival analysis and univariate analysis were investigated. (3) Results: Median follow-up was 20 months. Median OS was 24 months. One-year FFLP and one-year OS were 100% and 90.7%, respectively. Median PFS was 18 months, and one-year PFS was 72.2%. Twenty-five patients (46.3%) were alive at the time of analysis, and both median FU and OS for this subgroup were 26 months. No acute/late toxicity > G2 was reported. (4) Conclusions: SABR for LAPC using Calypso® presented as an effective and safe treatment and could be a promising local therapeutic option with very acceptable toxicity, either as a single treatment or in a multimodality regimen. Dose escalation to the tumor combined with systemic treatment could yield better clinical outcomes.
PET-CT in Clinical Adult Oncology: II. Primary Thoracic and Breast Malignancies
Authors: Covington Matthew F. , Koppula Bhasker R. , Fine Gabriel C. , Salem Ahmed Ebada , Wiggins Richard H. , Hoffman John M. , Morton Kathryn A.
Published: May 2022

Positron emission tomography combined with x-ray computed tomography (PET-CT) is an advanced imaging modality with oncologic applications that include staging, therapy assessment, restaging, and surveillance. This six-part series of review articles provides practical information to providers and imaging professionals regarding the best use of PET-CT for the more common adult malignancies. The second article of this series addresses primary thoracic malignancy and breast cancer. For primary thoracic malignancy, the focus will be on lung cancer, malignant pleural mesothelioma, thymoma, and thymic carcinoma, with an emphasis on the use of FDG PET-CT. For breast cancer, the various histologic subtypes will be addressed, and will include 18F fluorodeoxyglucose (FDG), recently Food and Drug Administration (FDA)-approved 18F-fluoroestradiol (FES), and 18F sodium fluoride (NaF). The pitfalls and nuances of PET-CT in breast and primary thoracic malignancies and the imaging features that distinguish between subcategories of these tumors are addressed. This review will serve as a resource for the appropriate roles and limitations of PET-CT in the clinical management of patients with breast and primary thoracic malignancies for healthcare professionals caring for adult patients with these cancers. It also serves as a practical guide for imaging providers, including radiologists, nuclear medicine physicians, and their trainees.
Differential Impacts on Tensional Homeostasis of Gastric Cancer Cells Due to Distinct Domain Variants of E-Cadherin
Authors: Xu Han , Bunde Katie A. , Figueiredo Joana , Seruca Raquel , Smith Michael L. , Stamenović Dimitrije
Published: May 2022

In epithelia, breakdown of tensional homeostasis is closely associated with E-cadherin dysfunction and disruption of tissue function and integrity. In this study, we investigated the effect of E-cadherin mutations affecting distinct protein domains on tensional homeostasis of gastric cancer cells. We used micropattern traction microscopy to measure temporal fluctuations of cellular traction forces in AGS cells transfected with the wild-type E-cadherin or with variants affecting the extracellular, the juxtamembrane, and the intracellular domains of the protein. We focused on the dynamic aspect of tensional homeostasis, namely the ability of cells to maintain a consistent level of tension, with low temporal variability around a set point. Cells were cultured on hydrogels micropatterned with different extracellular matrix (ECM) proteins to test whether the ECM adhesion impacts cell behavior. A combination of Fibronectin and Vitronectin was used as a substrate that promotes the adhesive ability of E-cadherin dysfunctional cells, whereas Collagen VI was used to test an unfavorable ECM condition. Our results showed that mutations affecting distinct E-cadherin domains influenced differently cell tensional homeostasis, and pinpointed the juxtamembrane and intracellular regions of E-cadherin as the key players in this process. Furthermore, Fibronectin and Vitronectin might modulate cancer cell behavior towards tensional homeostasis.
Activation of Peroxydisulfate by Bimetallic Nano Zero-Valent Iron for Waste-Activated Sludge Disintegration
Authors: Socha Barbara , Silvestri Daniele , Grübel Klaudiusz , Padil Vinod V. T. , Dudziak Mariusz , Ghanbari Farshid , Černík Miroslav , Wacławek Stanisław
Published: May 2022

Waste-activated sludge (WAS) disintegration using peroxydisulfate (PDS) has attracted scientific attention over the past few years. Despite several advantages offered by a sulfate radical-advanced oxidation process, there are still too many downsides of this treatment that limit its facile large-scale application. This study investigated whether modifying nano zero-valent iron (nZVI) with a second metal such as Ag and Cu enhanced the disruption of WAS. The disintegration efficiency was assessed using standard techniques, i.e., soluble chemical oxygen demand, Fourier-transform infrared spectroscopy and a scanning electron microscope. The bimetallics were shown to have an improved disintegration efficiency of > 2.5-fold compared with the untreated sample. Furthermore, nZVI/Ag was found to be more efficient than nZVI/Cu for PDS activation, which was validated by the higher ratio (3 and 2.5 for nZVI/Ag and nZVI/Cu, respectively) between the soluble extracellular polymeric substances and the bound extracellular polymeric substances (S-EPS/B-EPS). Similar conclusions were derived from a SEM analysis. The improved disintegration efficiency could be related to the enhanced electron transfer from nZVI to PDS or the intrinsic properties of silver, which was found to be one of the best activators for PDS under homogeneous conditions. We believe that this study deepens the understanding of PDS heterogeneous activation processes.
The Anti-CGRP Antibody Fremanezumab Lowers CGRP Release from Rat Dura Mater and Meningeal Blood Flow
Authors: Dux Mária , Vogler Birgit , Kuhn Annette , Mackenzie Kimberly D. , Stratton Jennifer , Messlinger Karl
Published: May 2022

Monoclonal antibodies directed against the neuropeptide calcitonin gene-related peptide (CGRP) belong to a new generation of therapeutics that are effective in the prevention of migraine. CGRP, a potent vasodilator, is strongly implicated in the pathophysiology of migraine, but its role remains to be fully elucidated. The hemisected rat head preparation and laser Doppler flowmetry were used to examine the effects on CGRP release from the dura mater and meningeal blood flow of the subcutaneously injected anti-CGRP monoclonal antibody fremanezumab at 30 mg/kg, when compared to an isotype control antibody. Some rats were administered glycerol trinitrate (GTN) intraperitoneally to produce a migraine-like sensitized state. When compared to the control antibody, the fremanezumab injection was followed by reduced basal and capsaicin-evoked CGRP release from day 3 up to 30 days. The difference was enhanced after 4 h of GTN application. The samples from the female rats showed a higher CGRP release compared to that of the males. The increases in meningeal blood flow induced by acrolein (100 µM) and capsaicin (100 nM) were reduced 13–20 days after the fremanezumab injection, and the direct vasoconstrictor effect of high capsaicin (10 µM) was intensified. In conclusion, fremanezumab lowers the CGRP release and lasts up to four weeks, thereby lowering the CGRP-dependent meningeal blood flow. The antibody may not only prevent the released CGRP from binding but may also influence the CGRP release stimulated by noxious agents relevant for the generation of migraine pain.
CFTR Modulators in People with Cystic Fibrosis: Real-World Evidence in France
Authors: Regard Lucile , Martin Clémence , Burnet Espérie , Da Silva Jennifer , Burgel Pierre-Régis
Published: May 2022

Cystic fibrosis (CF) is a rare genetic multisystemic disease, the manifestations of which are due to mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein and can lead to respiratory insufficiency and premature death. CFTR modulators, which were developed in the past decade, partially restore CFTR protein function. Their clinical efficacy has been demonstrated in phase 3 clinical trials, particularly in terms of lung function and pulmonary exacerbations, nutritional status, and quality of life in people with gating mutations (ivacaftor), homozygous for the F508del mutation (lumacaftor/ivacaftor and tezacaftor/ivacaftor), and in those with at least one F508del mutation (elexacaftor/tezacaftor/ivacaftor). However, many questions remain regarding their long-term safety and effectiveness, particularly in patients with advanced lung disease, liver disease, renal insufficiency, or problematic bacterial colonization. The impact of CFTR modulators on other important outcomes such as concurrent treatments, lung transplantation, chest imaging, or pregnancies also warrants further investigation. The French CF Reference Network includes 47 CF centers that contribute patient data to the comprehensive French CF Registry and have conducted nationwide real-world studies on CFTR modulators. This review seeks to summarize the results of these real-world studies and examine their findings against those of randomized control trials.
Functional Deficits of 5×FAD Neural Stem Cells Are Ameliorated by Glutathione Peroxidase 4
Authors: Dar Nawab John , Na Ren , Ran Qitao
Published: May 2022

Alzheimer’s disease (AD) is the most common cause of dementia affecting millions of people around the globe. Impaired neurogenesis is reported in AD as well as in AD animal models, although the underlying mechanism remains unclear. Elevated lipid peroxidation products are well-documented in AD. In current study, the role of lipid peroxidation on neural stem cell (NSCs) function is tested. Neural stem cells (NSCs) from 5×FAD mice, a widely used AD model with impaired neurogenesis, were observed to have increased levels of lipid reactive oxygen species compared to NSCs from control WT mice. 5×FAD NSCs exhibited altered differentiation potential as revealed by their propensity to differentiate into astrocytic lineage instead of neuronal lineage compared to WT NSCs. In addition, 5×FAD NSCs showed a reduced level of Gpx4, a key enzyme in reducing hydroperoxides in membrane lipids, and this reduction appeared to be caused by enhanced autophagy-lysosomal degradation of Gpx4 protein. To test if increasing Gpx4 could restore differentiation potential, NSCs from 5×FAD and Gpx4 double transgenic mice, i.e., 5×FAD/GPX4 mice were studied. Remarkably, upon differentiation, neuronal linage cells increased significantly in 5×FAD/GPX4 cultures compared to 5×FAD cultures. Taken together, the findings suggest that deficiency of lipid peroxidation defense contributes to functional decline of NSCs in AD.
Cigarette Smoke Extract Disturbs Mitochondria-Regulated Airway Epithelial Cell Responses to Pneumococci
Authors: Aghapour Mahyar , Tulen Christy B. M. , Abdi Sarabi Mohsen , Weinert Sönke , Müsken Mathias , Relja Borna , van Schooten Frederik-Jan , Jeron Andreas , Braun-Dullaeus Rüdiger , Remels Alexander H. , Bruder Dunja
Published: May 2022

Mitochondrial functionality is crucial for the execution of physiologic functions of metabolically active cells in the respiratory tract including airway epithelial cells (AECs). Cigarette smoke is known to impair mitochondrial function in AECs. However, the potential contribution of mitochondrial dysfunction in AECs to airway infection and airway epithelial barrier dysfunction is unknown. In this study, we used an in vitro model based on AECs exposed to cigarette smoke extract (CSE) followed by an infection with Streptococcus pneumoniae (Sp). The levels of oxidative stress as an indicator of mitochondrial stress were quantified upon CSE and Sp treatment. In addition, expression of proteins associated with mitophagy, mitochondrial content, and biogenesis as well as mitochondrial fission and fusion was quantified. Transcriptional AEC profiling was performed to identify the potential changes in innate immune pathways and correlate them with indices of mitochondrial function. We observed that CSE exposure substantially altered mitochondrial function in AECs by suppressing mitochondrial complex protein levels, reducing mitochondrial membrane potential and increasing mitochondrial stress and mitophagy. Moreover, CSE-induced mitochondrial dysfunction correlated with reduced enrichment of genes involved in apical junctions and innate immune responses to Sp, particularly type I interferon responses. Together, our results demonstrated that CSE-induced mitochondrial dysfunction may contribute to impaired innate immune responses to Sp.
Peroxiredoxin, Senescence, and Cancer
Authors: Wu Mengyao , Deng Chujun , Lo Tak-Ho , Chan Ka-Ying , Li Xiang , Wong Chi-Ming
Published: May 2022

Peroxiredoxins are multifunctional enzymes that play a key role in protecting cells from stresses and maintaining the homeostasis of many cellular processes. Peroxiredoxins were firstly identified as antioxidant enzymes that can be found in all living organisms. Later studies demonstrated that peroxiredoxins also act as redox signaling regulators, chaperones, and proinflammatory factors and play important roles in oxidative defense, redox signaling, protein folding, cycle cell progression, DNA integrity, inflammation, and carcinogenesis. The versatility of peroxiredoxins is mainly based on their unique active center cysteine with a wide range of redox states and the ability to switch between low- and high-molecular-weight species for regulating their peroxidase and chaperone activities. Understanding the molecular mechanisms of peroxiredoxin in these processes will allow the development of new approaches to enhance longevity and to treat various cancers. In this article, we briefly review the history of peroxiredoxins, summarize recent advances in our understanding of peroxiredoxins in aging- and cancer-related biological processes, and discuss the future perspectives of using peroxiredoxins in disease diagnostics and treatments.
The Extracellular Matrix Proteins Tenascin-C and Tenascin-R Retard Oligodendrocyte Precursor Maturation and Myelin Regeneration in a Cuprizone-Induced Long-Term Demyelination Animal Model
Authors: Bauch Juliane , Faissner Andreas
Published: May 2022

Oligodendrocytes are the myelinating cells of the central nervous system. The physiological importance of oligodendrocytes is highlighted by diseases such as multiple sclerosis, in which the myelin sheaths are degraded and the axonal signal transmission is compromised. In a healthy brain, spontaneous remyelination is rare, and newly formed myelin sheaths are thinner and shorter than the former ones. The myelination process requires the migration, proliferation, and differentiation of oligodendrocyte precursor cells (OPCs) and is influenced by proteins of the extracellular matrix (ECM), which consists of a network of glycoproteins and proteoglycans. In particular, the glycoprotein tenascin-C (Tnc) has an inhibitory effect on the differentiation of OPCs and the remyelination efficiency of oligodendrocytes. The structurally similar tenascin-R (Tnr) exerts an inhibitory influence on the formation of myelin membranes in vitro. When Tnc knockout oligodendrocytes were applied to an in vitro myelination assay using artificial fibers, a higher number of sheaths per single cell were obtained compared to the wild-type control. This effect was enhanced by adding brain-derived neurotrophic factor (BDNF) to the culture system. Tnr−/− oligodendrocytes behaved differently in that the number of formed sheaths per single cell was decreased, indicating that Tnr supports the differentiation of OPCs. In order to study the functions of tenascin proteins in vivo Tnc−/− and Tnr−/− mice were exposed to Cuprizone-induced demyelination for a period of 10 weeks. Both Tnc−/− and Tnr−/− mouse knockout lines displayed a significant increase in the regenerating myelin sheath thickness after Cuprizone treatment. Furthermore, in the absence of either tenascin, the number of OPCs was increased. These results suggest that the fine-tuning of myelin regeneration is regulated by the major tenascin proteins of the CNS.
Hedgehog Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling
Authors: Zeng Ling-Hui , Barkat Muhammad Qasim , Syed Shahzada Khurram , Shah Shahid , Abbas Ghulam , Xu Chengyun , Mahdy Amina , Hussain Nadia , Hussain Liaqat , Majeed Abdul , Khan Kashif-ur-Rehman , Wu Ximei , Hussain Musaddique
Published: May 2022

The development of the embryonic lung demands complex endodermal–mesodermal interactions, which are regulated by a variety of signaling proteins. Hedgehog (Hh) signaling is vital for lung development. It plays a key regulatory role during several morphogenic mechanisms, such as cell growth, differentiation, migration, and persistence of cells. On the other hand, abnormal expression or loss of regulation of Hh signaling leads to airway asthmatic remodeling, which is characterized by cellular matrix modification in the respiratory system, goblet cell hyperplasia, deposition of collagen, epithelial cell apoptosis, proliferation, and activation of fibroblasts. Hh also targets some of the pathogens and seems to have a significant function in tissue repairment and immune-related disorders. Similarly, aberrant Hh signaling expression is critically associated with the etiology of a variety of other airway lung diseases, mainly, bronchial or tissue fibrosis, lung cancer, and pulmonary arterial hypertension, suggesting that controlled regulation of Hh signaling is crucial to retain healthy lung functioning. Moreover, shreds of evidence imply that the Hh signaling pathway links to lung organogenesis and asthmatic airway remodeling. Here, we compiled all up-to-date investigations linked with the role of Hh signaling in the development of lungs as well as the attribution of Hh signaling in impairment of lung expansion, airway remodeling, and immune response. In addition, we included all current investigational and therapeutic approaches to treat airway asthmatic remodeling and immune system pathway diseases.
Centrosome Positioning in Migrating Dictyostelium Cells
Authors: Ishikawa-Ankerhold Hellen , Kroll Janina , Heuvel Dominic van den , Renkawitz Jörg , Müller-Taubenberger Annette
Published: May 2022

Directional cell migration and the establishment of polarity play an important role in development, wound healing, and host cell defense. While actin polymerization provides the driving force at the cell front, the microtubule network assumes a regulatory function, in coordinating front protrusion and rear retraction. By using Dictyostelium discoideum cells as a model for amoeboid movement in different 2D and 3D environments, the position of the centrosome relative to the nucleus was analyzed using live-cell microscopy. Our results showed that the centrosome was preferentially located rearward of the nucleus under all conditions tested for directed migration, while the nucleus was oriented toward the expanding front. When cells are hindered from straight movement by obstacles, the centrosome is displaced temporarily from its rearward location to the side of the nucleus, but is reoriented within seconds. This relocalization is supported by the presence of intact microtubules and their contact with the cortex. The data suggest that the centrosome is responsible for coordinating microtubules with respect to the nucleus. In summary, we have analyzed the orientation of the centrosome during different modes of migration in an amoeboid model and present evidence that the basic principles of centrosome positioning and movement are conserved between Dictyostelium and human leukocytes.