bluuebunny/crossref_metadata_2025 huggingface dataset:
Benzaldehyde Attenuates the Fifth Stage Larval Excretory–Secretory Product of Angiostrongylus cantonensis-Induced Injury in Mouse Astrocytes via Regulation of Endoplasmic Reticulum Stress and Oxidative Stress
Authors: Chen Kuang-Yao , Chen Yi-Ju , Cheng Chien-Ju , Jhan Kai-Yuan , Wang Lian-Chen
Published: January 2022

Excretory–secretory products (ESPs) are the main research targets for investigating the hosts and helminths interaction. Parasitic worms can migrate to parasitic sites and avoid the host immune response by secreting this product. Angiostrongylus cantonensis is an important food-borne zoonotic parasite that causes severe neuropathological damage and symptoms, including eosinophilic meningitis or meningoencephalitis in humans. Benzaldehydes are organic compounds composed of a benzene ring and formyl substituents. This compound has anti-inflammatory and antioxidation properties. Previous studies showed that 3-hydroxybenzaldehyde (3-HBA) and 4-hydroxybenzaldehyde (4-HBA) can reduce apoptosis in A. cantonensis ESP-treated astrocytes. These results on the protective effect underlying benzaldehyde have primarily focused on cell survival. The study was designed to investigate the molecular mechanisms of endoplasmic reticulum stress (ER stress) and oxidative stress in astrocytes in A. cantonensis ESP-treated astrocytes and to evaluate the therapeutic consequent of 3-HBA and 4-HBA. First, we initially established the RNA-seq dataset in each group, including normal, ESPs, ESPs + 3-HBA, and ESPs + 4-HBA. We also found that benzaldehyde (3-HBA and 4-HBA) can stimulate astrocytes to express ER stress-related molecules after ESP treatment. The level of oxidative stress could also be decreased in astrocytes by elevating antioxidant activity and reducing ROS generation. These results suggested that benzaldehyde may be a potential therapeutic compound for human angiostrongyliasis to support brain cell survival by inducing the expression levels of ER stress- and oxidative stress-related pathways.
MiR-182-5p Modulates Prostate Cancer Aggressive Phenotypes by Targeting EMT Associated Pathways
Authors: Souza Marilesia Ferreira , Cólus Ilce Mara Syllos , Fonseca Aline Simoneti , Antunes Valquíria Casanova , Kumar Deepak , Cavalli Luciane Regina
Published: January 2022

Prostate cancer (PCa) is a clinically heterogeneous disease, where deregulation of epigenetic events, such as miRNA expression alterations, are determinants for its development and progression. MiR-182-5p, a member of the miR-183 family, when overexpressed has been associated with PCa tumor progression and decreased patients’ survival rates. In this study, we determined the regulatory role of miR-182-5p in modulating aggressive tumor phenotypes in androgen-refractory PCa cell lines (PC3 and DU-145). The transient transfection of the cell lines with miR-182-5p inhibitor and mimic systems, significantly affected cell proliferation, adhesion, migration, and the viability of the cells to the chemotherapeutic agents, docetaxel, and abiraterone. It also affected the protein expression levels of the tumor progression marker pAKT. These changes, however, were differentially observed in the cell lines studied. A comprehensive biological and functional enrichment analysis and miRNA/mRNA interaction revealed its strong involvement in the epithelial-mesenchymal transition (EMT) process; expression analysis of EMT markers in the PCa transfected cells directly or indirectly modulated the analyzed tumor phenotypes. In conclusion, miR-182-5p differentially impacts tumorigenesis in androgen-refractory PCa cells, in a compatible oncomiR mode of action by targeting EMT-associated pathways.
Looking at COVID-19 from a Systems Biology Perspective
Authors: Turilli Emily Samuela , Lualdi Marta , Fasano Mauro
Published: January 2022

The sudden outbreak and worldwide spread of the SARS-CoV-2 pandemic pushed the scientific community to find fast solutions to cope with the health emergency. COVID-19 complexity, in terms of clinical outcomes, severity, and response to therapy suggested the use of multifactorial strategies, characteristic of the network medicine, to approach the study of the pathobiology. Proteomics and interactomics especially allow to generate datasets that, reduced and represented in the forms of networks, can be analyzed with the tools of systems biology to unveil specific pathways central to virus–human host interaction. Moreover, artificial intelligence tools can be implemented for the identification of druggable targets and drug repurposing. In this review article, we provide an overview of the results obtained so far, from a systems biology perspective, in the understanding of COVID-19 pathobiology and virus–host interactions, and in the development of disease classifiers and tools for drug repurposing.
Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies
Authors: Genovesi Sacha , Moro Riccardo , Vignoli Beatrice , De Felice Dario , Canossa Marco , Montironi Rodolfo , Carbone Francesco Giuseppe , Barbareschi Mattia , Lunardi Andrea , Alaimo Alessandro
Published: January 2022

Metastatic prostate cancer (mPCa) is one of the leading causes of cancer-related mortality in both the US and Europe. Androgen deprivation is the first-line therapy for mPCa; however, resistance to therapy inevitably occurs and the disease progresses to the castration resistant stage, which is uncurable. A definition of novel targeted therapies is necessary for the establishment of innovative and more effective protocols of personalized oncology. We employed genetically engineered mouse models of PCa and human samples to characterize the expression of the TRPM8 cation channel in both hormone naïve and castration resistant tumors. We show that Trpm8 expression marks both indolent (Pten-null) and aggressive (Pten/Trp53 double-null and TRAMP) mouse prostate adenocarcinomas. Importantly, both mouse and human castration-resistant PCa preserve TRPM8 protein expression. Finally, we tested the effect of TRPM8 agonist D-3263 administration in combination with enzalutamide or docetaxel on the viability of aggressive mouse PCa cell lines. Our data demonstrate that D-3263 substantially enhances the pro-apoptotic activity of enzalutamide and docetaxel in TRAMP-C1 e TRAMP-C2 PCa cell lines. To conclude, this study provides the basis for pre-clinical in vivo testing of TRPM8 targeting as a novel strategy to implement the efficacy of standard-of-care treatments for advanced PCa.
Folate-Targeted Liposomal Formulations Improve Effects of Methotrexate in Murine Collagen-Induced Arthritis
Authors: Guimarães Diana , Lager Franck , Renault Gilles , Guezguez Jamil , Burnet Michael , Cunha Joana , Cavaco-Paulo Artur , Nogueira Eugénia
Published: January 2022

Methotrexate (MTX) is first-line therapy for the treatment of rheumatoid arthritis (RA), however, its use may be limited by side effects notably post-injection malaise. When patients are intolerant or become unresponsive, second-line or antibody therapy may be indicated. A folate-targeted liposomal formulation of MTX (FL-MTX) is tropic to arthritic paws and prevents the onset of collagen-induced arthritis (CIA) in the mouse. We optimized the drug-to-lipid molar ratio to 0.15 and demonstrated the therapeutic efficacy of this form at 2 mg/kg MTX intraperitoneal (i.p.) twice a week. These improved liposomes were present in inflamed joints in proportion to the degree of swelling of the paw and bone remodeling activity. FL-MTX had lower hepatic and renal elimination of MTX than the free substance. FL-MTX provided equivalent results when given i.p. or subcutaneous (s.c.) and FL-MTX 2 mg/kg (drug/lipid 0.15), twice weekly, was similar to or more effective than 35 mg/kg MTX (same route and schedule) in reducing the incidence and swelling in the murine CIA model. These results suggest that FL-MTX is a more potent nanotherapeutic formulation than free MTX treatment. Its potential benefits for patients may include reduced frequency of treatment and lower overall doses for a given response.
Role of ADCC, CDC, and CDCC in Vaccine-Mediated Protection against Her2 Mammary Carcinogenesis
Authors: Macagno Marco , Bandini Silvio , Bolli Elisabetta , Bello Amanda , Riccardo Federica , Barutello Giuseppina , Merighi Irene Fiore , Forni Guido , Lamolinara Alessia , Del Pizzo Francesco , Iezzi Manuela , Cavallo Federica , Conti Laura , Quaglino Elena
Published: January 2022

Amplification or mutation of the Her2 oncoantigen in human mammary glands leads to the development of an aggressive breast carcinoma. Several features of this breast carcinoma are reproduced in mammary carcinomas that spontaneously arise in female transgenic mice bearing the activated rat Her2 oncogene under transcriptional control of the mouse mammary tumor virus promoter-BALB-neuT (neuT) mice. We previously demonstrated that carcinoma progression in neuT mice can be prevented by DNA vaccination with RHuT, a plasmid coding for a chimeric rat/human Her2 protein. RHuT vaccination exerts an antitumor effect, mostly mediated by the induction of a strong anti-rat Her2 antibody response. IgG induced by RHuT vaccine mainly acts by blocking Her2 signaling, thus impairing cell cycle progression and inducing apoptosis of cancer cells, but other indirect effector mechanisms could be involved in the antibody-mediated protection. The recruitment of cells with perforin-dependent cytotoxic activity, able to perform antibody-dependent cellular cytotoxicity, has already been investigated. Less is known about the role of the complement system in sustaining antitumor response through complement-dependent cytotoxicity and cellular cytotoxicity in vaccinated mice. This work highlights that the weight of such mechanisms in RHuT-induced cancer protection is different in transplantable versus autochthonous Her2+ tumor models. These results may shed new light on the effector mechanisms involved in antibody-dependent anti-cancer responses, which might be exploited to ameliorate the therapy of Her2+ breast cancer.
Are Neurophysiological Biomarkers Able to Discriminate Multiple Sclerosis Clinical Subtypes?
Authors: Belvisi Daniele , Tartaglia Matteo , Borriello Giovanna , Baione Viola , Crisafulli Sebastiano Giuseppe , Zuccoli Valeria , Leodori Giorgio , Ianniello Antonio , Pasqua Gabriele , Pantano Patrizia , Berardelli Alfredo , Pozzilli Carlo , Conte Antonella
Published: January 2022

Secondary progressive multiple sclerosis (SPMS) subtype is retrospectively diagnosed, and biomarkers of the SPMS are not available. We aimed to identify possible neurophysiological markers exploring grey matter structures that could be used in clinical practice to better identify SPMS. Fifty-five people with MS and 31 healthy controls underwent a transcranial magnetic stimulation protocol to test intracortical interneuron excitability in the primary motor cortex and somatosensory temporal discrimination threshold (STDT) to test sensory function encoded in cortical and deep grey matter nuclei. A logistic regression model was used to identify a combined neurophysiological index associated with the SP subtype. We observed that short intracortical inhibition (SICI) and STDT were the only variables that differentiated the RR from the SP subtype. The logistic regression model provided a formula to compute the probability of a subject being assigned to an SP subtype based on age and combined SICI and STDT values. While only STDT correlated with disability level at baseline evaluation, both SICI and STDT were associated with disability at follow-up. SICI and STDT abnormalities reflect age-dependent grey matter neurodegenerative processes that likely play a role in SPMS pathophysiology and may represent easily accessible neurophysiological biomarkers for the SPMS subtype.
SERS Liquid Biopsy Profiling of Serum for the Diagnosis of Kidney Cancer
Authors: Moisoiu Tudor , Iancu Stefania D. , Burghelea Dan , Dragomir Mihnea P. , Iacob Gheorghita , Stefancu Andrei , Cozan Ramona G. , Antal Oana , Bálint Zoltán , Muntean Valentin , Badea Radu I. , Licarete Emilia , Leopold Nicolae , Elec Florin I.
Published: January 2022

Renal cancer (RC) represents 3% of all cancers, with a 2% annual increase in incidence worldwide, opening the discussion about the need for screening. However, no established screening tool currently exists for RC. To tackle this issue, we assessed surface-enhanced Raman scattering (SERS) profiling of serum as a liquid biopsy strategy to detect renal cell carcinoma (RCC), the most prevalent histologic subtype of RC. Thus, serum samples were collected from 23 patients with RCC and 27 controls (CTRL) presenting with a benign urological pathology such as lithiasis or benign prostatic hypertrophy. SERS profiling of deproteinized serum yielded SERS band spectra attributed mainly to purine metabolites, which exhibited higher intensities in the RCC group, and Raman bands of carotenoids, which exhibited lower intensities in the RCC group. Principal component analysis (PCA) of the SERS spectra showed a tendency for the unsupervised clustering of the two groups. Next, three machine learning algorithms (random forest, kNN, naïve Bayes) were implemented as supervised classification algorithms for achieving discrimination between the RCC and CTRL groups, yielding an AUC of 0.78 for random forest, 0.78 for kNN, and 0.76 for naïve Bayes (average AUC 0.77 ± 0.01). The present study highlights the potential of SERS liquid biopsy as a diagnostic and screening strategy for RCC. Further studies involving large cohorts and other urologic malignancies as controls are needed to validate the proposed SERS approach.
Decreased SLC27A5 Suppresses Lipid Synthesis and Tyrosine Metabolism to Activate the Cell Cycle in Hepatocellular Carcinoma
Authors: Wang Jiyan , Qiao Yaya , Sun Huanran , Chang Hongkai , Zhao Huifang , Zhang Shuai , Shan Changliang
Published: January 2022

Tyrosine is an essential ketogenic and glycogenic amino acid for the human body, which means that tyrosine is not only involved in protein metabolism, but also participates in the metabolism of lipids and carbohydrates. The liver is an important place for metabolism of lipids, carbohydrates, and proteins. The metabolic process of biological macro-molecules is a basis for maintaining the physiological activities of organisms, but the cross-linking mechanism of these processes is still unclear. Here, we found that the tyrosine-metabolizing enzymes, which were specifically and highly expressed in the liver, were significantly down-regulated in hepatocellular carcinoma (HCC), and had a correlation with a poor prognosis of HCC patients. Further analysis found that the reduction of tyrosine metabolism would activate the cell cycle and promote cell proliferation. In addition, we also found that the solute carrier family 27 member 5 (SLC27A5) regulates the expression of tyrosine-metabolizing enzymes through nuclear factor erythroid 2-related factor 2 (NRF2). Therefore, the SLC27A5 and tyrosine-metabolizing enzymes that we have identified coordinate lipid and tyrosine metabolism, regulate the cell cycle, and are potential targets for cancer treatment.
What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes
Authors: Palicelli Andrea , Croci Stefania , Bisagni Alessandra , Zanetti Eleonora , De Biase Dario , Melli Beatrice , Sanguedolce Francesca , Ragazzi Moira , Zanelli Magda , Chaux Alcides , Cañete-Portillo Sofia , Bonasoni Maria Paola , Ascani Stefano , De Leo Antonio , Giordano Guido , Landriscina Matteo , Carrieri Giuseppe , Cormio Luigi , Gandhi Jatin , Nicoli Davide , Farnetti Enrico , Piana Simonetta , Tafuni Alessandro , Bonacini Martina
Published: January 2022

Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). BRCA1/2 loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to BRCA-mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with BRCA1/2 or ATM somatic mutations had higher response rates to pembrolizumab. PTEN regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/BRCA/PTEN statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored BRCA1/2 aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. SPOP mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.
Profiling Microglia in a Mouse Model of Machado–Joseph Disease
Authors: Campos Ana Bela , Duarte-Silva Sara , Fernandes Bruno , das Neves Sofia Pereira , Marques Fernanda , Teixeira-Castro Andreia , Neves-Carvalho Andreia , Monteiro-Fernandes Daniela , Portugal Camila Cabral , Socodato Renato , Summavielle Teresa , Ambrósio António Francisco , Relvas João Bettencourt , Maciel Patrícia
Published: January 2022

Microglia have been increasingly implicated in neurodegenerative diseases (NDs), and specific disease associated microglia (DAM) profiles have been defined for several of these NDs. Yet, the microglial profile in Machado–Joseph disease (MJD) remains unexplored. Here, we characterized the profile of microglia in the CMVMJD135 mouse model of MJD. This characterization was performed using primary microglial cultures and microglial cells obtained from disease-relevant brain regions of neonatal and adult CMVMJD135 mice, respectively. Machine learning models were implemented to identify potential clusters of microglia based on their morphological features, and an RNA-sequencing analysis was performed to identify molecular perturbations and potential therapeutic targets. Our findings reveal morphological alterations that point to an increased activation state of microglia in CMVMJD135 mice and a disease-specific transcriptional profile of MJD microglia, encompassing a total of 101 differentially expressed genes, with enrichment in molecular pathways related to oxidative stress, immune response, cell proliferation, cell death, and lipid metabolism. Overall, these results allowed us to define the cellular and molecular profile of MJD-associated microglia and to identify genes and pathways that might represent potential therapeutic targets for this disorder.
Microfluidic Compartmentalization Platforms for Single Cell Analysis
Authors: Luo Xuhao , Chen Jui-Yi , Ataei Marzieh , Lee Abraham
Published: January 2022

Many cellular analytical technologies measure only the average response from a cell population with an assumption that a clonal population is homogenous. The ensemble measurement often masks the difference among individual cells that can lead to misinterpretation. The advent of microfluidic technology has revolutionized single-cell analysis through precise manipulation of liquid and compartmentalizing single cells in small volumes (pico- to nano-liter). Due to its advantages from miniaturization, microfluidic systems offer an array of capabilities to study genomics, transcriptomics, and proteomics of a large number of individual cells. In this regard, microfluidic systems have emerged as a powerful technology to uncover cellular heterogeneity and expand the depth and breadth of single-cell analysis. This review will focus on recent developments of three microfluidic compartmentalization platforms (microvalve, microwell, and microdroplets) that target single-cell analysis spanning from proteomics to genomics. We also compare and contrast these three microfluidic platforms and discuss their respective advantages and disadvantages in single-cell analysis.
Different Language Modalities Yet Similar Cognitive Processes in Arithmetic Fact Retrieval
Authors: Berteletti Ilaria , Kimbley Sarah E. , Sullivan SaraBeth J. , Quandt Lorna C. , Miyakoshi Makoto
Published: January 2022

Does experience with signed language impact the neurocognitive processes recruited by adults solving arithmetic problems? We used event-related potentials (ERPs) to identify the components that are modulated by operation type and problem size in Deaf American Sign Language (ASL) native signers and in hearing English-speaking participants. Participants were presented with single-digit subtraction and multiplication problems in a delayed verification task. Problem size was manipulated in small and large problems with an additional extra-large subtraction condition to equate the overall magnitude of large multiplication problems. Results show comparable behavioral results and similar ERP dissociations across groups. First, an early operation type effect is observed around 200 ms post-problem onset, suggesting that both groups have a similar attentional differentiation for processing subtraction and multiplication problems. Second, for the posterior-occipital component between 240 ms and 300 ms, subtraction problems show a similar modulation with problem size in both groups, suggesting that only subtraction problems recruit quantity-related processes. Control analyses exclude possible perceptual and cross-operation magnitude-related effects. These results are the first evidence that the two operation types rely on distinct cognitive processes within the ASL native signing population and that they are equivalent to those observed in the English-speaking population.
Imaging Clinical Subtypes and Associated Brain Networks in Alzheimer’s Disease
Authors: Herholz Karl
Published: January 2022

Alzheimer’s disease (AD) does not present uniform symptoms or a uniform rate of progression in all cases. The classification of subtypes can be based on clinical symptoms or patterns of pathological brain alterations. Imaging techniques may allow for the identification of AD subtypes and their differentiation from other neurodegenerative diseases already at an early stage. In this review, the strengths and weaknesses of current clinical imaging methods are described. These include positron emission tomography (PET) to image cerebral glucose metabolism and pathological amyloid or tau deposits. Magnetic resonance imaging (MRI) is more widely available than PET. It provides information on structural or functional changes in brain networks and their relation to AD subtypes. Amyloid PET provides a very early marker of AD but does not distinguish between AD subtypes. Regional patterns of pathology related to AD subtypes are observed with tau and glucose PET, and eventually as atrophy patterns on MRI. Structural and functional network changes occur early in AD but have not yet provided diagnostic specificity.
Multimedia Interventions for Neurodiversity: Leveraging Insights from Developmental Cognitive Neuroscience to Build an Innovative Practice
Authors: Farroni Teresa , Valori Irene , Carnevali Laura
Published: January 2022

Multimedia technologies and virtual reality offer unique possibilities to manipulate sensory, motor, interpersonal, and cognitive processes contributing to atypical developmental trajectories, thus holding an explosive potential to design innovative and engaging interventions. However, there has been little progress in developing interventions that go beyond the patient’s diagnosis or the fascination of technology and rather spring from a deep understanding of the specific neuropsychological processes to be nurtured in individuals. This perspective paper outlines how recent insights from developmental cognitive neuroscience can be leveraged to promote children’s multidimensional development and highlight future directions and challenges for innovating both research and clinical practice. Finally, we focus on some practical examples of multimedia and virtual reality activities we have designed to stimulate bodily-self experiences, which are crucial for building up a coherent sense of self and lay the foundation for interacting with the external world. Atypical bodily self is an early marker of heterogeneous neurodevelopmental conditions (such as autism spectrum disorders) and seems to be under-targeted in research and clinical approaches.
Kenny Music Performance Anxiety Inventory: Contribution for the Portuguese Validation
Authors: Dias Pedro , Veríssimo Lurdes , Figueiredo Nânci , Oliveira-Silva Patrícia , Serra Sofia , Coimbra Daniela
Published: January 2022

(1) Background: The aim of the present study was to contribute to the validation of the Portuguese version of the Kenny Music Performance Anxiety Inventory (K-MPAI) and to study its psychometric properties. (2) Methods: A sample of 164 undergraduate music students in Portugal (62.2% female; mean age = 22.63; SD = 4.36) completed an online survey composed of the K-MPAI Portuguese version, the State Trait Anxiety Inventory, and a sociodemographic questionnaire. The K-MPAI psychometric properties were examined using exploratory factor analyses, known-group differences, and Cronbach’s alpha. (3) Results: A four-factor structure was identified, in line with recent validation of this measure in other countries: music performance anxiety-related symptoms, depression and hopelessness, parental support, and memory self-efficacy. Concurrent and known-group validity were established, and reliability scores were appropriate for the dimensions and total score. (4) Conclusions: The results provide initial evidence of the appropriateness of the Portuguese version of the K-MPAI.
What Drives Construction Practitioners’ Acceptance of Intelligent Surveillance Systems? An Extended Technology Acceptance Model
Authors: Lu Ying , Deng Yunxuan
Published: January 2022

With the advent of intelligent construction, the intelligent surveillance system using computer vision technology has emerged as a prominent tool to identify unsafe behaviors on construction sites. At the same time, it is still viewed with suspicion by the construction industry, and its penetration rate remains low. To promote the successful implementation of the intelligent surveillance system, this study applied the technology acceptance model approach and developed an intelligent surveillance system acceptance model (ISSTAM) containing 12 variables from individual, organizational, environmental, and technical perspectives. Questionnaires were distributed to construction industry practitioners, 220 of whom provided valid data. Moreover, a structural equation model (SEM) was established for hypothesis testing. The research results suggest that job relevance, government action, training, and technical support positively and indirectly influence the use intention. Meanwhile, perceived usefulness, perceived ease of use, and cost savings directly and positively affect use intention, while privacy risk is verified to have a negative impact upon use intention. This study can help the government, organizations, and technology developers better apply the intelligent surveillance system to improve safety management levels.
Multifactorial Chloride Ingress Model for Reinforced Concrete Structures Subjected to Unsaturated Conditions
Authors: Zacchei Enrico , Bastidas-Arteaga Emilio
Published: January 2022

The attack of chloride ions is one of the most important factors affecting reinforced concrete (RC) durability. Chloride ingress into concrete is usually studied by assuming constant diffusivity and constant surface chloride concentration. However, these two approximations could badly estimate the chloride concentration in RC structures and then the lifetime assessment. Several factors influence the chloride concentration and ingress mechanisms in the convection area. In this paper, a new multifactorial and multiphase model to account for some effects on chloride surface concentrations in the convection zone is proposed. 136 values have been collected to identify the position and the chloride concentration in the border between the diffusion and convection zones. In addition, a time-dependent multifactorial diffusivity is considered. Diffusivity, which is the key parameter of the mechanical diffusion accounts in this paper for the water/cement ratio, chloride binding, temperature, concrete age, internal humidity, concrete deformation, and damage. The surface chloride model considers environment humidity, temperature, superficial concrete irregularities, and convection area of concrete. Advanced numerical solutions have been carried out to consider space and time dependencies in the model. Results show that the error function-based solutions could underestimate the chloride concentration C for periods < 10 years and for concrete depths > 4.0 cm in comparison with the proposed model.
Primaquine as a Candidate for HHV-8-Associated Primary Effusion Lymphoma and Kaposi’s Sarcoma Treatment
Authors: Gothland Adélie , Leducq Valentin , Grange Philippe , Faye Ousmane , Beauvais Remigereau Laurianne , Sayon Sophie , Désiré Nathalie , Jary Aude , Laplantine Emmanuel , Maiga Almoustapha Issiaka , Dupin Nicolas , Marcelin Anne-Geneviève , Calvez Vincent
Published: January 2022

Human Herpesvirus 8 (HHV-8) is associated with three main severe orphan malignancies, Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD), and primary effusion lymphoma (PEL), which present few therapeutic options. We identified the antimalarial primaquine diphosphate (PQ) as a promising therapeutic candidate for HHV-8-associated PEL and KS. Indeed, PQ strongly reduced cell viability through caspase-dependent apoptosis, specifically in HHV-8-infected PEL cells. Reactive oxygen species (ROS)- and endoplasmic reticulum (ER) stress-mediated apoptosis signaling pathways were found to be part of the in vitro cytotoxic effect of PQ. Moreover, PQ treatment had a clinically positive effect in a nonobese diabetic (NOD)/SCID xenograft PEL mouse model, showing a reduction in tumor growth and an improvement in survival. Finally, an exploratory proof-of-concept clinical trial in four patients harboring severe KS was conducted, with the main objectives to assess the efficacy, the safety, and the tolerability of PQ, and which demonstrated a positive efficacy on Kaposi’s sarcoma-related lesions and lymphedema.
Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma
Authors: Roalsø Marcus T. T. , Hald Øyvind H. , Alexeeva Marina , Søreide Kjetil
Published: January 2022

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to modulate and possibly enhance immune-based treatments. Epigenetic marks can also serve as diagnostic screening tools, as epigenetic changes occur at early stages of the disease. Further, epigenetics can be used in prognostication. The field is evolving, and this review seeks to provide an updated overview of the emerging role of epigenetics in the diagnosis, treatment, and prognostication of PDAC.
Metabolic Features of Tumor Dormancy: Possible Therapeutic Strategies
Authors: Pranzini Erica , Raugei Giovanni , Taddei Maria Letizia
Published: January 2022

Tumor relapse represents one of the main obstacles to cancer treatment. Many patients experience cancer relapse even decades from the primary tumor eradication, developing more aggressive and metastatic disease. This phenomenon is associated with the emergence of dormant cancer cells, characterized by cell cycle arrest and largely insensitive to conventional anti-cancer therapies. These rare and elusive cells may regain proliferative abilities upon the induction of cell-intrinsic and extrinsic factors, thus fueling tumor re-growth and metastasis formation. The molecular mechanisms underlying the maintenance of resistant dormant cells and their awakening are intriguing but, currently, still largely unknown. However, increasing evidence recently underlined a strong dependency of cell cycle progression to metabolic adaptations of cancer cells. Even if dormant cells are frequently characterized by a general metabolic slowdown and an increased ability to cope with oxidative stress, different factors, such as extracellular matrix composition, stromal cells influence, and nutrient availability, may dictate specific changes in dormant cells, finally resulting in tumor relapse. The main topic of this review is deciphering the role of the metabolic pathways involved in tumor cells dormancy to provide new strategies for selectively targeting these cells to prevent fatal recurrence and maximize therapeutic benefit.
Investigating the Potential of Isolating and Expanding Tumour-Infiltrating Lymphocytes from Adult Sarcoma
Authors: Ko Alice , Coward Victoria S. , Gokgoz Nalan , Dickson Brendan C. , Tsoi Kim , Wunder Jay S. , Andrulis Irene L.
Published: January 2022

Sarcomas are a heterogeneous group of mesenchymal neoplasms, many of which are associated with a high risk of metastasis and poor prognosis. Conventional chemotherapy and targeted therapies have varying effects across individuals and tumour subtypes. The current therapies frequently provide limited clinical benefit; hence, more effective treatments are urgently needed. Recent advances in immunotherapy, such as checkpoint inhibition or adoptive cell therapy (ACT), show potential in increasing efficacy by providing a more personalized treatment. Therapy with tumour-infiltrating lymphocytes (TILs) is an emerging field in immunotherapy. Here, we collected 190 sarcoma tumour specimens from patients without pre-operative adjuvant treatment in order to isolate TILs. We compared different methods of TIL expansion and optimized a protocol specifically for efficacy in culturing TILs from sarcoma. The expanded TIL populations were characterized by flow cytometry analysis using CD3, CD4, CD8, CD14, CD19 and CD56 markers. The TIL populations were non-specifically stimulated to establish TIL reactivity. Through an optimized expansion protocol, TILs were isolated and cultured from 54 of 92 primary sarcoma specimens. The isolated TILs varied in CD4+ and CD8+ T-cell compositions and retained their ability to release IFNγ upon stimulation. Our results suggest that certain sarcoma subtypes have the potential to yield a sufficient number of TILs for TIL therapy.
Kras Gene Analysis Using Liquid-Based Cytology Specimens Predicts Therapeutic Responses and Prognosis in Patients with Pancreatic Cancer
Authors: Itonaga Masahiro , Ashida Reiko , Murata Shin-Ichi , Yamashita Yasunobu , Hatamaru Keiichi , Tamura Takashi , Kawaji Yuki , Kayama Yuudai , Emori Tomoya , Kawai Manabu , Yamaue Hiroki , Matsuzaki Ibu , Nagai Hirokazu , Kinoshita Yuichi , Wan Ke , Shimokawa Toshio , Kitano Masayuki
Published: January 2022

Background: Although several molecular analyses have shown that the Kras gene status is related to long-term survival of patients with pancreatic ductal adenocarcinoma (PDAC), the results remain controversial. Here, we examined the Kras gene status in a cohort of unresectable PDAC patients who underwent first-line therapy with gemcitabine and nab-paclitaxel (GA) and assessed differences in chemotherapy responses and survival. Methods: Patients with a histological diagnosis of PDAC (based on EUS-guided fine-needle aspiration) from 2017 to 2019 were enrolled. Tumor genomic DNA was extracted from residual liquid-based cytology specimens and Kras mutations were assessed using the quenching probe method. The relationships between the Kras status and progression-free survival (PFS) and overall survival (OS) were assessed. Results: Of the 110 patients analyzed, 15 had wild-type Kras. Those with the wild-type gene showed significantly longer PFS and OS than those with mutant Kras (6.9/5.3 months (p = 0.044) vs. 19.9/11.8 months (p = 0.037), respectively). Multivariate analyses identified wild-type Kras as a significant independent factor associated with longer PFS and OS (HR = 0.53 (p = 0.045) and HR = 0.35 (p = 0.007), respectively). Conclusions: The analysis of the Kras gene status could be used to predict therapeutic responses to GA and prognosis in unresectable PDAC patients.
Advancing Cancer Treatment by Targeting Glutamine Metabolism—A Roadmap
Authors: Halama Anna , Suhre Karsten
Published: January 2022

Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.
Spine Metastases in Immunocompromised Mice after Intracardiac Injection of MDA-MB-231-SCP2 Breast Cancer Cells
Authors: Brylka Laura , Jähn-Rickert Katharina , Baranowsky Anke , Neven Mona , Horn Michael , Yorgan Timur , Wikman Harriet , Werner Stefan , Lübke Andreas , Amling Michael , Busse Björn , Pantel Klaus , Schinke Thorsten
Published: January 2022

Breast cancer cells frequently metastasize to bone, where their interaction with bone remodeling cell types enhances osteolytic bone destruction. Importantly, however, whereas skeletal analyses of xenograft models are usually restricted to hindlimb bones, human skeletal metastases are far more frequent in the spine, where trabecular bone mass is higher compared to femur or tibia. Here, we addressed whether breast cancer cells injected into immunocompromised mice metastasize to the spine and if this process is influenced by the amount of trabecular bone. We also took advantage of mice carrying the Col1a1-Krm2 transgene, which display severe osteoporosis. After crossing this transgene into the immunocompromised NSG background we injected MDA-MB-231-SCP2 breast cancer cells and analyzed their distribution three weeks thereafter. We identified more tumor cells and clusters of different size in spine sections than in femora, which allowed influences on bone remodeling cell types to be analyzed by comparing tumor-free to tumor-burdened areas. Unexpectedly, the Col1a1-Krm2 transgene did not affect spreading and metastatic outgrowth of MDA-MB-231-SCP2 cells, suggesting that bone tumor interactions are more relevant at later stages of metastatic progression.
Tumor Metabolism Is Affected by Obesity in Preclinical Models of Triple-Negative Breast Cancer
Authors: Yelek Caner , Mignion Lionel , Paquot Adrien , Bouzin Caroline , Corbet Cyril , Muccioli Giulio G. , Cani Patrice D. , Jordan Bénédicte F.
Published: January 2022

Obesity is characterized by an excessive fat mass accumulation associated with multiple disorders, including impaired glucose homeostasis, altered adipokine levels, and hyperlipidemia. Despite clear associations between tumor progression and obesity, the effects of these disorders on tumor metabolism remain largely unknown. Thus, we studied the metabolic differences between tumors of obese and lean mice in murine models of triple-negative breast cancer (E0771 and PY8819). For this purpose, a real-time hyperpolarized 1-13C-pyruvate-to-lactate conversion was studied before and after glucose administration in fasting mice. This work was completed by U-13C glucose tracing experiments using nuclear magnetic resonance (NMR) spectroscopy, as well as mass spectrometry (MS). Ex vivo analyses included immunostainings of major lipid, glucose, and monocarboxylic acids transporters. On the one hand, we discovered that tumors of obese mice yield higher lactate/pyruvate ratios after glucose administration. On the other hand, we found that the same tumors produce higher levels of lactate and alanine from glucose than tumors from lean mice, while no differences on the expression of key transporters associated with glycolysis (i.e., GLUT1, MCT1, MCT4) have been observed. In conclusion, our data suggests that breast tumor metabolism is regulated by the host’s physiological status, such as obesity and diabetes.
Implications of Stemness Features in 1059 Hepatocellular Carcinoma Patients from Five Cohorts: Prognosis, Treatment Response, and Identification of Potential Compounds
Authors: Mai Haoming , Xie Haisheng , Luo Mengqi , Hou Jia , Chen Jiaxuan , Hou Jinlin , Jiang De-ke
Published: January 2022

Cancer stemness has been reported to drive hepatocellular carcinoma (HCC) tumorigenesis and treatment resistance. In this study, five HCC cohorts with 1059 patients were collected to calculate transcriptional stemness indexes (mRNAsi) by the one-class logistic regression machine learning algorithm. In the TCGA-LIHC cohort, we found mRNAsi was an independent prognostic factor, and 626 mRNAsi-related genes were identified by Spearman correlation analysis. The HCC stemness risk model (HSRM) was trained in the TCGA-LIHC cohort and significantly discriminated overall survival in four independent cohorts. HSRM was also significantly associated with transarterial chemoembolization treatment response and rapid tumor growth in HCC patients. Consensus clustering was conducted based on mRNAsi-related genes to divide 1059 patients into two stemness subtypes. On gene set variation analysis, samples of subtype I were found enriched with pathways such as DNA replication and cell cycle, while several liver-specific metabolic pathways were inhibited in these samples. Somatic mutation analysis revealed more frequent mutations of TP53 and RB1 in the subtype I samples. In silico analysis suggested topoisomerase, cyclin-dependent kinase, and histone deacetylase as potential targets to inhibit HCC stemness. In vitro assay showed two predicted compounds, Aminopurvalanol-a and NCH-51, effectively suppressed oncosphere formation and impaired viability of HCC cell lines, which may shed new light on HCC treatment.
Impact of Progressive Site-Directed Therapy in Oligometastatic Castration-Resistant Prostate Cancer on Subsequent Treatment Response
Authors: Yoshida Soichiro , Takahara Taro , Arita Yuki , Toda Kazuma , Kimura Koichiro , Tanaka Hajime , Yokoyama Minato , Matsuoka Yoh , Yoshimura Ryoichi , Fujii Yasuhisa
Published: January 2022

The purpose of this study was to evaluate the impact of progressive site-directed therapy (PSDT) for oligometastatic castration-resistant prostate cancer (OM-CRPC) on the efficacy of subsequent androgen receptor axis-targeted (ARAT) drugs, and to demonstrate the possibility of prolonging overall survival (OS). We performed a retrospective analysis of 15 OM-CRPC patients who underwent PSDT and subsequently received first-line ARAT drugs (PSDT group) and 13 OM-CRPC patients who were treated with first-line ARAT drugs without PSDT (non-PSDT group). PSDT was performed with the intention of treating all progressing sites detected by whole-body diffusion-weighted MRI with radiotherapy. Thirteen patients (86.7%) treated with PSDT had a decrease in PSA levels, which was at least 50% in 10 (66.7%) patients. The median PSA progression-free survival (PFS) for PSDT was 7.4 months. The median PSA-PFS for ARAT was 27.2 months in patients in the PSDT group and 11.7 months in the non-PSDT group, with a significant difference between the two groups (hazard ratio [HR], 0.28; p = 0.010). The median OS was not reached in the PSDT group and was significantly longer than 44.5 months in the non-PSDT group (HR, 0.11; p = 0.014). In OM-CRPC, PSDT may improve the efficacy of subsequent ARAT and OS.
AKT1 Is Required for a Complete Palbociclib-Induced Senescence Phenotype in BRAF-V600E-Driven Human Melanoma
Authors: Bayer Abraham L. , Pietruska Jodie , Farrell Jaymes , McRee Siobhan , Alcaide Pilar , Hinds Philip W.
Published: January 2022

Cellular senescence is a carefully regulated process of proliferative arrest accompanied by functional and morphologic changes. Senescence allows damaged cells to avoid neoplastic proliferation; however, the induction of the senescence-associated secretory phenotype (SASP) can promote tumor growth. The complexity of senescence may limit the efficacy of anti-neoplastic agents, such as CDK4/6 inhibitors (Cdk4/6i), that induce a senescence-like state in tumor cells. The AKT kinase family, which contains three isoforms that play both unique and redundant roles in cancer progression, is commonly hyperactive in many cancers including melanoma and has been implicated in the regulation of senescence. To interrogate the role of AKT isoforms in Cdk4/6i-induced cellular senescence, we generated isoform-specific AKT knockout human melanoma cell lines. We found that the CDK4/6i Palbociclib induced a form of senescence in these cells that was dependent on AKT1. We then evaluated the activity of the cGAS-STING pathway, recently implicated in cellular senescence, finding that cGAS-STING function was dependent on AKT1, and pharmacologic inhibition of cGAS had little effect on senescence. However, we found SASP factors to require NF-κB function, in part dependent on a stimulatory phosphorylation of IKKα by AKT1. In summary, we provide the first evidence of a novel, isoform-specific role for AKT1 in therapy-induced senescence in human melanoma cells acting through NF-κB but independent of cGAS.