bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of the Escherichia coli HU Protein with Various Topological Forms of DNA
Authors: Huang Li , Zhang Zhenfeng , McMacken Roger
Published: November 2021

E. coli histone-like protein HU has been shown to interact with different topological forms of DNA. Using radiolabeled HU, we examine the effects of DNA supercoiling on HU–DNA interactions. We show that HU binds preferentially to negatively supercoiled DNA and that the affinity of HU for DNA increases with increases in the negative superhelical density of DNA. Binding of HU to DNA is most sensitively influenced by DNA supercoiling within a narrow but physiologically relevant range of superhelicity (σ = −0.06–0). Under stoichiometric binding conditions, the affinity of HU for negatively supercoiled DNA (σ = −0.06) is more than 10 times higher than that for relaxed DNA at physiologically relevant HU/DNA mass ratios (e.g., 1:10). This binding preference, however, becomes negligible at HU/DNA mass ratios higher than 1:2. At saturation, HU binds both negatively supercoiled and relaxed DNA with similar stoichiometries, i.e., 5–6 base pairs per HU dimer. In our chemical crosslinking studies, we demonstrate that HU molecules bound to negatively supercoiled DNA are more readily crosslinked than those bound to linear DNA. At in vivo HU/DNA ratios, HU appears to exist predominantly in a tetrameric form on negatively supercoiled DNA and in a dimeric form on linear DNA. Using a DNA ligase-mediated nick closure assay, we show that approximately 20 HU dimers are required to constrain one negative supercoil on relaxed DNA. Although fewer HU dimers may be needed to constrain one negative supercoil on negatively supercoiled DNA, our results and estimates of the cellular level of HU argue against a major role for HU in constraining supercoils in vivo. We discuss our data within the context of the dynamic distribution of the HU protein in cells, where temporal and local changes of DNA supercoiling are known to take place.
Role of Inflammation and Redox Status on Doxorubicin-Induced Cardiotoxicity in Infant and Adult CD-1 Male Mice
Authors: Reis-Mendes Ana , Padrão Ana Isabel , Duarte José Alberto , Gonçalves-Monteiro Salomé , Duarte-Araújo Margarida , Remião Fernando , Carvalho Félix , Sousa Emília , Bastos Maria Lourdes , Costa Vera Marisa
Published: November 2021

Doxorubicin (DOX) is a topoisomerase II inhibitor commonly used in the treatment of several types of cancer. Despite its efficacy, DOX can potentially cause fatal adverse effects, like cardiotoxicity. This work aimed to assess the role of inflammation in DOX-treated infant and adult mice and its possible link to underlying cardiotoxicity. Two groups of CD-1 male mice of different ages (infants or adults) were subjected to biweekly DOX administrations, to reach a cumulative dose of 18.0 mg/kg, which corresponds approximately in humans to 100.6 mg/m2 for infants and 108.9 mg/m2 for adults a clinically relevant dose in humans. The classic plasmatic markers of cardiotoxicity increased, and that damage was confirmed by histopathological findings in both groups, although it was higher in adults. Moreover, in DOX-treated adults, an increase of cardiac fibrosis was observed, which was accompanied by an increase in specific inflammatory parameters, namely, macrophage M1 and nuclear factor kappa B (NF-κB) p65 subunit, with a trend toward increased levels of the tumor necrosis factor receptor 2 (TNFR2). On the other hand, the levels of myeloperoxidase (MPO) and interleukin (IL)-6 significantly decreased in DOX-treated adult animals. In infants, a significant increase in cardiac protein carbonylation and in the levels of nuclear factor erythroid-2 related factor 2 (Nrf2) was observed. In both groups, no differences were found in the levels of tumor necrosis factor (TNF-α), IL-1β, p38 mitogen-activated protein kinase (p38 MAPK) or NF-κB p52 subunit. In conclusion, using a clinically relevant dose of DOX, our study demonstrated that cardiac effects are associated not only with the intensity of the inflammatory response but also with redox response. Adult mice seemed to be more prone to DOX-induced cardiotoxicity by mechanisms related to inflammation, while infant mice seem to be protected from the damage caused by DOX, possibly by activating such antioxidant defenses as Nrf2.
808-nm Photobiomodulation Affects the Viability of a Head and Neck Squamous Carcinoma Cellular Model, Acting on Energy Metabolism and Oxidative Stress Production
Authors: Ravera Silvia , Bertola Nadia , Pasquale Claudio , Bruno Silvia , Benedicenti Stefano , Ferrando Sara , Zekiy Angelina , Arany Praveen , Amaroli Andrea
Published: November 2021

Photobiomodulation (PBM) is a form of low-dose light therapy that acts through energy delivery from non-ionizing sources. During the recent two decades, there has been tremendous progress with PBM acceptance in medicine. However, PBM effects on potential stimulation of existing malignant or pre-malignant cells remain unknown. Thus, the primary endpoint was to assess the safety of PBM treatment parameters on head and neck squamous cell carcinoma (HNSCC) proliferation or survival. The secondary endpoint was to assess any putative anti-cancer effects of PBM treatments. Cell viability, energy metabolism, oxidative stress, and pro- and anti-apoptotic markers expression were investigated on a Human Head and Neck Squamous Cell Carcinoma cellular model (OHSU-974 FAcorr cell line). PBM therapy was administered through the 810 nm diode laser (GaAlAs) device (Garda Laser, 7024 Negrar, Verona, Italy) at the powers of 0, 0.25, 0.50, 0.75, 1.00, or 1.25 W in continuous wave (CW) mode for an exposure time of 60 s with a spot-size of 1 cm2 and with a distance of 1.86 cm from the cells. Results showed that 810-nm PBM affected oxidative phosphorylation in OHSU-971 FAcorr, causing a metabolic switch to anaerobic glycolysis. In addition, PBM reduced the catalase activity, determining an unbalance between oxidative stress production and the antioxidant defenses, which could stimulate the pro-apoptotic cellular pathways. Our data, at the parameters investigated, suggest the safeness of PBM as a supportive cancer therapy. Pre-clinical and clinical studies are necessary to confirm the in vitro evidence.
Bioactive Flavonoids Icaritin and Icariin Protect against Cerebral Ischemia–Reperfusion-Associated Apoptosis and Extracellular Matrix Accumulation in an Ischemic Stroke Mouse Model
Authors: Wu Cheng-Tien , Chen Man-Chih , Liu Shing-Hwa , Yang Ting-Hua , Long Lin-Hwa , Guan Siao-Syun , Chen Chang-Mu
Published: November 2021

Stroke, which is the second leading cause of mortality in the world, is urgently needed to explore the medical strategies for ischemic stroke treatment. Both icariin (ICA) and icaritin (ICT) are the major active flavonoids extracted from Herba epimedii that have been regarded as the neuroprotective agents in disease models. In this study, we aimed to investigate and compare the neuroprotective effects of ICA and ICT in a middle cerebral artery occlusion (MCAO) mouse model. Male ICR mice were pretreated with both ICA and ICT, which ameliorated body weight loss, neurological injury, infarct volume, and pathological change in acute ischemic stroke mice. Furthermore, administration of both ICA and ICT could also protect against neuronal cell apoptotic death, oxidative and nitrosative stress, lipid peroxidation, and extracellular matrix (ECM) accumulation in the brains. The neuroprotective effects of ICT are slightly better than that of ICA in acute cerebral ischemic stroke mice. These results suggest that pretreatment with both ICA and ICT improves the neuronal cell apoptosis and responses of oxidative/nitrosative stress and counteracts the ECM accumulation in the brains of acute cerebral ischemic stroke mice. Both ICA and ICT treatment may serve as a useful therapeutic strategy for acute ischemic stroke.
The Insula: A Stimulating Island of the Brain
Authors: Rachidi Inès , Minotti Lorella , Martin Guillaume , Hoffmann Dominique , Bastin Julien , David Olivier , Kahane Philippe
Published: November 2021

Direct cortical stimulation (DCS) in epilepsy surgery patients has a long history of functional brain mapping and seizure triggering. Here, we review its findings when applied to the insula in order to map the insular functions, evaluate its local and distant connections, and trigger seizures. Clinical responses to insular DCS are frequent and diverse, showing a partial segregation with spatial overlap, including a posterior somatosensory, auditory, and vestibular part, a central olfactory-gustatory region, and an anterior visceral and cognitive-emotional portion. The study of cortico-cortical evoked potentials (CCEPs) has shown that the anterior (resp. posterior) insula has a higher connectivity rate with itself than with the posterior (resp. anterior) insula, and that both the anterior and posterior insula are closely connected, notably between the homologous insular subdivisions. All insular gyri show extensive and complex ipsilateral and contralateral extra-insular connections, more anteriorly for the anterior insula and more posteriorly for the posterior insula. As a rule, CCEPs propagate first and with a higher probability around the insular DCS site, then to the homologous region, and later to more distal regions with fast cortico-cortical axonal conduction delays. Seizures elicited by insular DCS have rarely been specifically studied, but their rate does not seem to differ from those of other DCS studies. They are mainly provoked from the insular seizure onset zone but can also be triggered by stimulating intra- and extra-insular early propagation zones. Overall, in line with the neuroimaging studies, insular DCS studies converge on the view that the insula is a multimodal functional hub with a fast propagation of information, whose organization helps understand where insular seizures start and how they propagate.
Relationship between Amyloid-β Deposition and the Coupling between Structural and Functional Brain Networks in Patients with Mild Cognitive Impairment and Alzheimer’s Disease
Authors: Zhang Hui , Hui Edward S. , Cao Peng , Mak Henry K. F.
Published: November 2021

Previous studies have demonstrated that the accumulation of amyloid-β (Aβ) pathologies has distinctive stage-specific effects on the structural and functional brain networks along the Alzheimer’s disease (AD) continuum. A more comprehensive account of both types of brain network may provide a better characterization of the stage-specific effects of Aβ pathologies. A potential candidate for this joint characterization is the coupling between the structural and functional brain networks (SC-FC coupling). We therefore investigated the effect of Aβ accumulation on global SC-FC coupling in patients with mild cognitive impairment (MCI), AD, and healthy controls. Patients with MCI were dichotomized according to their level of Aβ pathology seen in 18F-flutemetamol PET-CT scans—namely, Aβ-negative and Aβ-positive. Our results show that there was no difference in global SC-FC coupling between different cohorts. During the prodromal AD stage, there was a significant negative correlation between the level of Aβ pathology and the global SC-FC coupling of MCI patients with positive Aβ, but no significant correlation for MCI patients with negative Aβ. During the AD dementia stage, the correlation between Aβ pathology and global SC-FC coupling in patients with AD was positive. Our results suggest that Aβ pathology has distinctive stage-specific effects on global coupling between the structural and functional brain networks along the AD continuum.
Football as an Alternative to Work on the Development of Social Skills in Children with Autism Spectrum Disorder with Level 1
Authors: Lopez-Diaz Jose Maria , Felgueras Custodio Nerea , Garrote Camarena Inmaculada
Published: November 2021

Given the characteristics of people with Autism Spectrum Disorder, it is evident the difficulties they show in the development of social skills. The scarce participation of people with Autism Spectrum Disorder in group sports can be taken as a reference. The aim of this study was to analyse the impact of football on the development of social skills in children with Autism Spectrum Disorder. In order to measure the sporting impact, it was necessary to implement a football training programme with the intention of evaluating different social skills. Thirteen children participated in the programme, all of them with a diagnosis of Autism Spectrum Disorder and with a severity level of 1. The study was based on a pre-experimental, pre-test/post-test design. Non-parametric tests were used for the statistical analysis, applying the Wilcoxon test. Two specific tools on social skills were used for data collection. The results showed a generalised improvement in the dimensions linked to the social skills assessed. This highlights the possibility of considering group sport as an alternative to be taken into account to work on and enhance social skills in children with Autism Spectrum Disorder.
Deep Convolutional Neural Networks Detect Tumor Genotype from Pathological Tissue Images in Gastrointestinal Stromal Tumors
Authors: Liang Cher-Wei , Fang Pei-Wei , Huang Hsuan-Ying , Lo Chung-Ming
Published: November 2021

Gastrointestinal stromal tumors (GIST) are common mesenchymal tumors, and their effective treatment depends upon the mutational subtype of the KIT/PDGFRA genes. We established deep convolutional neural network (DCNN) models to rapidly predict drug-sensitive mutation subtypes from images of pathological tissue. A total of 5153 pathological images of 365 different GISTs from three different laboratories were collected and divided into training and validation sets. A transfer learning mechanism based on DCNN was used with four different network architectures, to identify cases with drug-sensitive mutations. The accuracy ranged from 87% to 75%. Cross-institutional inconsistency, however, was observed. Using gray-scale images resulted in a 7% drop in accuracy (accuracy 80%, sensitivity 87%, specificity 73%). Using images containing only nuclei (accuracy 81%, sensitivity 87%, specificity 73%) or cytoplasm (accuracy 79%, sensitivity 88%, specificity 67%) produced 6% and 8% drops in accuracy rate, respectively, suggesting buffering effects across subcellular components in DCNN interpretation. The proposed DCNN model successfully inferred cases with drug-sensitive mutations with high accuracy. The contribution of image color and subcellular components was also revealed. These results will help to generate a cheaper and quicker screening method for tumor gene testing.
Interventional Radiology Image-Guided Locoregional Therapies (LRTs) and Immunotherapy for the Treatment of HCC
Authors: Biondetti Pierpaolo , Saggiante Lorenzo , Ierardi Anna Maria , Iavarone Massimo , Sangiovanni Angelo , Pesapane Filippo , Fumarola Enrico Maria , Lampertico Pietro , Carrafiello Gianpaolo
Published: November 2021

Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor microenvironment with potential systemic effects. Nevertheless, the immune activation against HCC induced by LRTs is not strong enough on its own to generate a systemic significant antitumor response, and it is incapable of preventing tumor recurrence. Currently, there is great interest in the possibility of combining LRTs with immunotherapy for HCC, as this combination may result in a mutually beneficial and synergistic relationship. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of LRTs, reducing recurrence cases and improving outcome. On the other hand, LTRs counteract the typical immunosuppressive HCC microenvironment and status and could therefore enhance the efficacy of immunotherapy. Here, after reviewing the current therapeutic options for HCC, we focus on LRTs, describing for each of them the technique and data on its effect on the immune system. Then, we describe the current status of immunotherapy and finally report the recently published and ongoing clinical studies testing this combination.
Tyrosine Kinase Inhibitors in Adult Glioblastoma: An (Un)Closed Chapter?
Authors: Aldaz Paula , Arozarena Imanol
Published: November 2021

Glioblastoma (GBM) is the most common and lethal form of malignant brain tumor. GBM patients normally undergo surgery plus adjuvant radiotherapy followed by chemotherapy. Numerous studies into the molecular events driving GBM highlight the central role played by the Epidermal Growth Factor Receptor (EGFR), as well as the Platelet-derived Growth Factor Receptors PDGFRA and PDGFRB in tumor initiation and progression. Despite strong preclinical evidence for the therapeutic potential of tyrosine kinase inhibitors (TKIs) that target EGFR, PDGFRs, and other tyrosine kinases, clinical trials performed during the last 20 years have not led to the desired therapeutic breakthrough for GBM patients. While clinical trials are still ongoing, in the medical community there is the perception of TKIs as a lost opportunity in the fight against GBM. In this article, we review the scientific rationale for the use of TKIs targeting glioma drivers. We critically analyze the potential causes for the failure of TKIs in the treatment of GBM, and we propose alternative approaches to the clinical evaluation of TKIs in GBM patients.
The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways
Authors: Liu Mingcheng , Huang Qingqing , A Jun , Li Linyue , Li Xiawei , Zhang Zhiqian , Dong Jin-Tang
Published: November 2021

Prostate cancer (PCa) is a leading cause of cancer-related deaths among men worldwide, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides represent an attractive group of candidates for anticancer repurposing, but the cardiac glycoside deslanoside has not been tested for potential anticancer activity so far. We found that deslanoside effectively inhibited colony formation in vitro and tumor growth in nude mice of PCa cell lines 22Rv1, PC-3, and DU 145. Such an anticancer activity was mediated by both the cell cycle arrest at G2/M and the induction of apoptosis, as demonstrated by different functional assays and the expression status of regulatory proteins of cell cycle and apoptosis in cultured cells. Moreover, deslanoside suppressed the invasion and migration of PCa cell lines. Genome-wide expression profiling and bioinformatic analyses revealed that 130 genes were either upregulated or downregulated by deslanoside in both 22Rv1 and PC-3 cell lines. These genes enriched multiple cellular processes, such as response to steroid hormones, regulation of lipid metabolism, epithelial cell proliferation and its regulation, and negative regulation of cell migration. They also enriched multiple signaling pathways, such as necroptosis, MAPK, NOD-like receptor, and focal adhesion. Survival analyses of the 130 genes in the TCGA PCa database revealed that 10 of the deslanoside-downregulated genes (ITG2B, CNIH2, FBF1, PABPC1L, MMP11, DUSP9, TMEM121, SOX18, CMPK2, and MAMDC4) inversely correlated, while one deslanoside-upregulated gene (RASD1) positively correlated, with disease-free survival in PCa patients. In addition, one deslanoside-downregulated gene (ENG) inversely correlated, while three upregulated genes (JUN, MXD1, and AQP3) positively correlated with overall survival in PCa patients. Some of the 15 genes have not been implicated in cancer before. These findings provide another candidate for repurposing cardiac glycosides for anticancer drugs. They also suggest that a diverse range of molecular events underlie deslanoside’s anticancer activity in PCa cells.
Epoxidation of 1,5,9-Cyclododecatriene with Hydrogen Peroxide over Ti-MCM-41 Catalyst
Authors: Wróblewska Agnieszka , Kujbida Marcin , Lewandowski Grzegorz , Kamińska Adrianna , Koren Zvi C. , Michalkiewicz Beata
Published: November 2021

This work presents the results of our research on the epoxidation of 1,5,9-cyclododecatriene (CDT) with hydrogen peroxide over the Ti-MCM-41 catalyst. The influence of the following parameters on the course of the process was investigated: temperature, CDT:H2O2 molar ratio, solvent composition and its type, and catalyst content. The highest selectivity of CDT transformation to 1,2-epoxy-5,9-cyclododecadiene (ECDD)—approximately 100 mol%, the highest yet reported—was obtained at the CDT conversion of 13 mol% and with the following parameter values: a catalyst content of 5 wt%; a molar ratio of CDT:H2O2 = 2; isopropyl alcohol (i-PrOH) as the solvent, with a composition of 80 wt% in the reaction mixture; a temperature of 80 °C; and a reaction time of 240 min. The highest conversion of CDT (37 mol%) was obtained at the ECDD selectivity of 56 mol% and using the following process parameters: a catalyst content of 5 wt%; a molar ratio of CDT:H2O2 = 0.5; i-PrOH used as the solvent, with solvent composition of 80 wt%; a temperature of 80 °C; and a reaction time of 60 min. It should be emphasized that the CDT conversion obtained in the current study is higher (by 9 mol%) than that described in the literature on heterogeneous catalysts.
A Boron Delivery Antibody (BDA) with Boronated Specific Residues: New Perspectives in Boron Neutron Capture Therapy from an In Silico Investigation
Authors: Rondina Alessandro , Fossa Paola , Orro Alessandro , Milanesi Luciano , De Palma Antonella , Perico Davide , Mauri Pier Luigi , D’Ursi Pasqualina
Published: November 2021

Boron Neutron Capture Therapy (BNCT) is a tumor cell-selective radiotherapy based on a nuclear reaction that occurs when the isotope boron-10 (10B) is radiated by low-energy thermal neutrons or epithermal neutrons, triggering a nuclear fission response and enabling a selective administration of irradiation to cells. Hence, we need to create novel delivery agents containing 10B with high tumor selectivity, but also exhibiting low intrinsic toxicity, fast clearance from normal tissue and blood, and no pharmaceutical effects. In the past, boronated monoclonal antibodies have been proposed using large boron-containing molecules or dendrimers, but with no investigations in relation to maintaining antibody specificity and structural and functional features. This work aims at improving the potential of monoclonal antibodies applied to BNCT therapy, identifying in silico the best native residues suitable to be substituted with a boronated one, carefully evaluating the effect of boronation on the 3D structure of the monoclonal antibody and on its binding affinity. A boronated monoclonal antibody was thus generated for specific 10B delivery. In this context, we have developed a case study of Boron Delivery Antibody Identification Pipeline, which has been tested on cetuximab. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer.
IL-1β and TNFα Cooperativity in Regulating IL-6 Expression in Adipocytes Depends on CREB Binding and H3K14 Acetylation
Authors: Al-Roub Areej , Al Madhoun Ashraf , Akhter Nadeem , Thomas Reeby , Miranda Lavina , Jacob Texy , Al-Ozairi Ebaa , Al-Mulla Fahd , Sindhu Sardar , Ahmad Rasheed
Published: November 2021

IL-6 was found to be overexpressed in the adipose tissue of obese individuals, which may cause insulin resistance. However, the regulation of IL-6 in adipocytes in obesity setting remains to be explored. Since IL-1β and TNFα are increased in obese adipose tissue and promote inflammation, we investigated whether cooperation between IL-1β and TNFα influences the production of IL-6. Our data show that IL-1β and TNFα cooperatively enhance IL-6 expression in 3T3L-1 adipocytes. Similar results were seen in human adipocytes isolated from subcutaneous and visceral fat. Although adipocytes isolated from lean and obese adipose tissues showed similar responses for production of IL-6 when incubated with IL-1β/TNFα, secretion of IL-6 was higher in adipocytes from obese tissue. TNFα treatment enhanced CREB binding at CRE locus, which was further enhanced with IL-1β, and was associated with elevated histone acetylation at CRE locus. On the other hand, IL-1β treatments mediated C/EBPβ binding to NF-IL-6 consensus, but not sufficiently to mediate significant histone acetylation. Interestingly, treatment with both stimulatory factors amplifies CREB binding and H3K14 acetylation. Furthermore, histone acetylation inhibition by anacardic acid or curcumin reduces IL-6 production. Notably, inhibition of histone deacetylase (HDAC) activity by trichostatin A (TSA) resulted in the further elevation of IL-6 expression in response to combined treatment of adipocytes with IL-1β and TNFα. In conclusion, our results show that there is an additive interaction between IL-1β and TNFα that depends on CREB binding and H3K14 acetylation, and leads to the elevation of IL-6 expression in adipocytes, providing interesting pathophysiological connection among IL-1β, TNFα, and IL-6 in settings such as obesity.
Incremental Experience in In Vitro Primary Culture of Human Pulmonary Arterial Endothelial Cells Harvested from Swan-Ganz Pulmonary Arterial Catheters
Authors: Tielemans Birger , Stoian Leanda , Wagenaar Allard , Leys Mathias , Belge Catharina , Delcroix Marion , Quarck Rozenn
Published: November 2021

Pulmonary arterial hypertension (PAH) is a devastating condition affecting the pulmonary microvascular wall and endothelium, resulting in their partial or total obstruction. Despite a combination of expensive vasodilatory therapies, mortality remains high. Personalized therapeutic approaches, based on access to patient material to unravel patient specificities, could move the field forward. An innovative technique involving harvesting pulmonary arterial endothelial cells (PAECs) at the time of diagnosis was recently described. The aim of the present study was to fine-tune the initial technique and to phenotype the evolution of PAECs in vitro subcultures. PAECs were harvested from Swan-Ganz pulmonary arterial catheters during routine diagnostic or follow up right heart catheterization. Collected PAECs were phenotyped by flow cytometry and immunofluorescence focusing on endothelial-specific markers. We highlight the ability to harvest patients’ PAECs and to maintain them for up to 7–12 subcultures. By tracking the endothelial phenotype, we observed that PAECs could maintain an endothelial phenotype for several weeks in culture. The present study highlights the unique opportunity to obtain homogeneous subcultures of primary PAECs from patients at diagnosis and follow-up. In addition, it opens promising perspectives regarding tailored precision medicine for patients suffering from rare pulmonary vascular diseases.
From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma
Authors: Anker Jonathan , Miller Justin , Taylor Nicole , Kyprianou Natasha , Tsao Che-Kai
Published: November 2021

Immunotherapy has revolutionized the treatment landscape for many cancer types. The treatment for renal cell carcinoma (RCC) has especially evolved in recent years, from cytokine-based immunotherapies to immune checkpoint inhibitors. Although clinical benefit from immunotherapy is limited to a subset of patients, many combination-based approaches have led to improved outcomes. The success of such approaches is a direct result of the tumor immunology knowledge accrued regarding the RCC microenvironment, which, while highly immunogenic, demonstrates many unique characteristics. Ongoing translational work has elucidated some of the mechanisms of response, as well as primary and secondary resistance, to immunotherapy. Here, we provide a comprehensive review of the RCC immunophenotype with a specific focus on how preclinical and clinical data are shaping the future of immunotherapy.
Gliogenic Potential of Single Pallial Radial Glial Cells in Lower Cortical Layers
Authors: Ojalvo-Sanz Ana Cristina , López-Mascaraque Laura
Published: November 2021

During embryonic development, progenitor cells are progressively restricted in their potential to generate different neural cells. A specific progenitor cell type, the radial glial cells, divides symmetrically and then asymmetrically to produce neurons, astrocytes, oligodendrocytes, and NG2-glia in the cerebral cortex. However, the potential of individual progenitors to form glial lineages remains poorly understood. To further investigate the cell progeny of single pallial GFAP-expressing progenitors, we used the in vivo genetic lineage-tracing method, the UbC-(GFAP-PB)-StarTrack. After targeting those progenitors in embryonic mice brains, we tracked their adult glial progeny in lower cortical layers. Clonal analyses revealed the presence of clones containing sibling cells of either a glial cell type (uniform clones) or two different glial cell types (mixed clones). Further, the clonal size and rostro-caudal cell dispersion of sibling cells differed depending on the cell type. We concluded that pallial E14 neural progenitors are a heterogeneous cell population with respect to which glial cell type they produce, as well as the clonal size of their cell progeny.
Challenges to Learners in Interpreting Self as Other, Post COVID-19
Authors: Nash Carol
Published: November 2021

The COVID-19 pandemic has prompted continuing constraints on the ability of students to interact with teachers and peers. Regarding this imposed segregation, what has not been considered is the effect of learners seeing self as other. With respect to augmentations of their body in interpersonal space by, (1) extending the body through witnessing themselves regularly in videoconferencing learning sessions, (2) isolating the body as a result of spending time apart from peers, social distancing at home, and (3) protecting the body through required mask-wearing where learners now consider who they represent in a mask, there are three important ways in which learners have felt unable to recognize themselves as they did pre-COVID-19. This migration from self to other, involving ingroup/outgroup distinctions, will be investigated from a number of perspectives—both sociological and psychological. Why the turning of self into other is problematic to the psyche will be discussed, as will the possible consequences for this ongoing lack of learner recognition long term, including focus on the new norms or embracing self-directed learning. Based on this analysis, the type of mentorship by teachers and parents that may be appropriate for helping learners contend with these changes will be recommended.
Decreasing Hypothermia-Related Escalation of Care in Newborn Infants Using the BEMPU TempWatch: A Randomised Controlled Trial
Authors: Lei Donna , Tan Kenneth , Malhotra Atul
Published: November 2021

Objective: To determine whether incorporating BEMPU TempWatch into the care of LBW/SGA neonates for continuous temperature monitoring decreases the rate of hypothermia requiring escalation of care. Methods: This was a randomised controlled trial conducted in a tertiary hospital in Melbourne, Australia. Participants were late preterm and term LBW/SGA neonates on the postnatal wards. Neonates were randomly assigned to receive either the BEMPU TempWatch in addition to standard care, or to receive standard care alone for the first 28 days of life. The primary outcome was hypothermia requiring escalation of care during initial hospital stay after birth. Results: Trial was discontinued after planned interim feasibility analysis, due to very low rates of hypothermia requiring escalation of care. In total, 75 neonates were included, with 36 in the intervention (TempWatch) group and 39 in the control group. The rate of hypothermia requiring escalation of care was 2/36 (5.6%) in the TempWatch group and 1/39 (2.6%) in the control group (relative risk (RR) 2.17, 95% CI 0.21 to 22.89). Rates of exclusive breastfeeding at discharge were 22/36 (61.1%) in the TempWatch and 13/39 (33.3%) in the control group (RR 1.83, 95% CI 1.10 to 3.07, p = 0.02). All other secondary outcomes were similar between the groups. Conclusions: Low rates of hypothermia requiring escalation of care in a tertiary, high-income setting meant it was not feasible for studying the effects of the TempWatch for this outcome. TempWatch may have a role in promoting exclusive breastfeeding, and this needs to be explored further.
Development of Microstructured Carbon Coatings by Substrate-Catalytic CVD
Authors: Pierpaoli Mattia , Sawczak Mirosław , Dettlaff Anna
Published: November 2021

Carbon nanostructured films were synthesized by chemical vapor deposition (CVD) on H18 stainless steel (AISI 440C) sheets with an H2/CH4/N2 gas mixture at various substrate temperatures. During the synthesis, the iron and chromium oxide layer was formed between the steel and carbonaceous layer. The carbon films exhibited wall-like and spherical morphologies and structures, as characterized by scanning electron microscopy and Raman spectroscopy. It was found that the synthesis temperature affects the microsphere density and, therefore, also in the electrochemical behavior. The electrochemical behavior of nanostructured carbon coatings strongly depends on the CVD deposition conditions. The best corrosion resistance (Rp = 11.8 MΩ·cm2, Icorr = 4.4 nA·cm−2) exhibits a nanostructured carbon sample with a moderate amount of sp2-C-rich carbon microspheres CμSs synthesized at 700 °C. The corrosion resistance of the nanostructured carbon coating is better than raw stainless steel.
Modelling and Prediction of the Spread of COVID-19 in Cameroon and Assessing the Governmental Measures (March–September 2020)
Authors: Nkague Nkamba Leontine , Manga Thomas Timothee
Published: November 2021

COVID-19 is an acute respiratory illness in humans caused by a coronavirus, capable of producing severe symptoms and, in some cases, death, especially in older people and those with underlying health conditions. It was originally identified in China in 2019 and became a pandemic in 2020. On 6 March 2020, Cameroon recorded its first cases of infection with COVID-19. The Government of Cameroon (GOC) took 13 barrier measures on 18 March 2020. On 1 May 2020, 19 new measures were adopted, easing restrictions and encouraging economic activity. On 1 June, schools and universities were reopened, after which massive screening began to take place throughout the country. In this study, we have modelled the COVID-19 epidemic in Cameroon in order to assess the governmental measures of response and predict the behaviour of epidemic As a result of these measures, the pandemic evolved in three phases. The first phase began on 18 March and ended on 15 May 2020. During this phase, the actual curve of cumulative positive cases based on field data closely fit the theoretical curve resulting from mathematical modelling. In the beginning of May, we predicted that nearly 3000 positive cases would be declared by mid-May 2020. The actual data confirmed these predictions: there were 2954 cases as of 15 May 2020. The second phase, beyond mid-May 2020, encompasses the period when the GOC’s relaxation of measures takes effect. This phase was marked by an acceleration of the cumulative number of positive cases starting in the third week of May, postponing the expected peak by two weeks. Under Phase 2 conditions, the onset of the peak will occur in early June and extend through the first two weeks of June. However, a third phase occurs in the first week of June, with the reopening of schools and universities combined with massive screening; the peak is therefore expected in the second week of June (around 15 June). The GOC should, at this stage, strengthen its response plan by tripling the current coverage capacity to regain the first phase convergence conditions associated with the first 13 measures. The pandemic will begin its descent in the month of august, but COVID-19 will remain endemic for at least one year.
A Method for Determining the Workability Diagram by Varying Friction Conditions in the Upsetting of a Cylinder between Flat Dies
Authors: Movrin Dejan , Milutinovic Mladomir , Vilotic Marko , Alexandrov Sergei , Lang Lihui
Published: November 2021

This paper aims to develop a method for determining the workability diagram by varying frictional conditions in the cylinder upsetting test. The method is based on a known theoretical relationship between the average stress triaxiality ratio and in-surface strains if the initiation of fracture occurs at a traction-free surface. This relationship is valid for any rigid/plastic strain hardening material obeying the Mises-type yield criterion and its associated flow rule, which shows the wide applicability of the method. The experimental input to the method is the strain path at the site of fracture initiation. Neither experimental nor numerical determination of stress components is required at this site, though the general ductile fracture criterion involves the linear and quadratic invariants of the stress tensor. The friction law’s formulation is neither required, though the friction stress is the agent for varying the state of stress and strain at the site of ductile fracture initiation. The upsetting tests are carried out on normalized medium-carbon steel C45E, for which the workability diagram is available from the literature. Comparison of the latter and the diagram found using the new method shows that the new method is reliable for determining a certain portion of the workability diagram.
Properties of AlN/GaN Heterostructures Grown at Low Growth Temperatures with Ammonia and Dimethylhydrazine
Authors: Reilly Caroline E. , Hatui Nirupam , Mates Thomas E. , Koirala Pratik , Oni Adedapo A. , Nakamura Shuji , DenBaars Steven P. , Keller Stacia
Published: November 2021

The integration of different electronic materials systems together has gained increasing interest in recent years, with the III-nitrides being a favorable choice for a variety of electronic applications. To increase flexibility in integration options, growing nitrides material directly on semi-processed wafers would be advantageous, necessitating low temperature (LT) growth schemes. In this work, the growth of AlN and GaN was conducted via metalorganic chemical vapor deposition (MOCVD) using both NH3 and DMHy as N-precursors. The relationships between growth rate versus temperature were determined within the range of 300 to 550 °C. The growth of AlN/GaN heterostructures was also investigated herein, employing flow modulation epitaxy MOCVD at 550 °C. Subsequent samples were studied via atomic force microscopy, X-ray diffraction, TEM, and Hall measurements. Two-dimensional electron gases were found in samples where the LT AlN layer was grown with NH3, with one sample showing high electron mobility and sheet charge of 540 cm2/V∙s and 3.76 × 1013 cm−2, respectively. Inserting a LT GaN layer under the LT AlN layer caused the mobility and charge to marginally decrease while still maintaining sufficiently high values. This sets the groundwork towards use of LT nitrides MOCVD in future electronic devices integrating III-nitrides with other materials.
Influence of V and Zn in FeCrCuMnTi High-Entropy Alloys on Microstructures and Uniaxial Compaction Behavior Prepared by Mechanical Alloying
Authors: Sivasankaran Subbarayan , Al-Mufadi Fahad A. , Ammar Hany R.
Published: November 2021

The densification behavior of FeCrCuMnTi (HEA1), FeCrCuMnTiV (HEA2), and FeCrCuMnTiVZn (HEA3) equiatomic high-entropy alloys (HEAs) was explored using different uniaxial quasi-static controlled compaction (1 mm/min). These HEAs were synthesized by mechanical alloying (MA, speed: 300 rpm, BPR: 10:1, time: 25 h). Various phase formations, structural characteristics (crystallite size, lattice strain, and lattice constant), thermo-dynamic calculations, powder surface morphologies, detailed microstructural evolutions, and chemical compositions were examined using X-ray diffraction, high-resolution scanning electron microscopy, and high-resolution transmission electron microscopy. The XRD results revealed the formation of multiple solid solutions (FCC, BCC, and HCP) due to the variation in entropy, and the presence of high-strength elements (Cr, Ti, and V) in the developed HEA alloys. The synthesized powders were consolidated into bulk green samples with different compaction pressures starting from 25 to 1100 MPa under as-milled and milled under stress recovery conditions (150 °C, 1 h). The incorporation of V in the FeCrCuMnTi HEA resulted in improved densification due to a greater reduction in particle size, and high configurational entropy. Furthermore, the stress-recovered powder samples produced more relative density owing to the elimination of lattice strain. Several linear and non-linear compaction models were applied to predict densification behavior. The non-linear Cooper and Eaton model produced the highest regression coefficients compared to the other models.
Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management
Authors: Simurda Tomas , Asselta Rosanna , Zolkova Jana , Brunclikova Monika , Dobrotova Miroslava , Kolkova Zuzana , Loderer Dusan , Skornova Ingrid , Hudecek Jan , Lasabova Zora , Stasko Jan , Kubisz Peter
Published: November 2021

Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.
Serum Biomarkers in Carotid Artery Disease
Authors: Kigka Vassiliki I. , Potsika Vassiliki , Mantzaris Michalis , Tsakanikas Vassilis , Koncar Igor , Fotiadis Dimitrios I.
Published: November 2021

Carotid artery disease is considered a major cause of strokes and there is a need for early disease detection and management. Although imaging techniques have been developed for the diagnosis of carotid artery disease and different imaging-based markers have been proposed for the characterization of atherosclerotic plaques, there is still need for a definition of high-risk plaques in asymptomatic patients who may benefit from surgical intervention. Measurement of circulating biomarkers is a promising method to assist in patient-specific disease management, but the lack of robust clinical evidence limits their use as a standard of care. The purpose of this review paper is to present circulating biomarkers related to carotid artery diagnosis and prognosis, which are mainly provided by statistical-based clinical studies. The result of our investigation showed that typical well-established inflammatory biomarkers and biomarkers related to patient lipid profiles are associated with carotid artery disease. In addition to this, more specialized types of biomarkers, such as endothelial and cell adhesion, matrix degrading, and metabolic biomarkers seem to be associated with different carotid artery disease outputs, assisting vascular specialists in selecting patients at high risk for stroke and in need of intervention.
Improving Skin Cancer Classification Using Heavy-Tailed Student T-Distribution in Generative Adversarial Networks (TED-GAN)
Authors: Ahmad Bilal , Jun Sun , Palade Vasile , You Qi , Mao Li , Zhongjie Mao
Published: November 2021

Deep learning has gained immense attention from researchers in medicine, especially in medical imaging. The main bottleneck is the unavailability of sufficiently large medical datasets required for the good performance of deep learning models. This paper proposes a new framework consisting of one variational autoencoder (VAE), two generative adversarial networks, and one auxiliary classifier to artificially generate realistic-looking skin lesion images and improve classification performance. We first train the encoder-decoder network to obtain the latent noise vector with the image manifold’s information and let the generative adversarial network sample the input from this informative noise vector in order to generate the skin lesion images. The use of informative noise allows the GAN to avoid mode collapse and creates faster convergence. To improve the diversity in the generated images, we use another GAN with an auxiliary classifier, which samples the noise vector from a heavy-tailed student t-distribution instead of a random noise Gaussian distribution. The proposed framework was named TED-GAN, with T from the t-distribution and ED from the encoder-decoder network which is part of the solution. The proposed framework could be used in a broad range of areas in medical imaging. We used it here to generate skin lesion images and have obtained an improved classification performance on the skin lesion classification task, rising from 66% average accuracy to 92.5%. The results show that TED-GAN has a better impact on the classification task because of its diverse range of generated images due to the use of a heavy-tailed t-distribution.
First Integrals of Shear-Free Fluids and Complexity
Authors: Gumede Sfundo C. , Govinder Keshlan S. , Maharaj Sunil D.
Published: November 2021

A single master equation governs the behaviour of shear-free neutral perfect fluid distributions arising in gravity theories. In this paper, we study the integrability of yxx=f(x)y2, find new solutions, and generate a new first integral. The first integral is subject to an integrability condition which is an integral equation which restricts the function f(x). We find that the integrability condition can be written as a third order differential equation whose solution can be expressed in terms of elementary functions and elliptic integrals. The solution of the integrability condition is generally given parametrically. A particular form of f(x)∼1x51−1x−15/7 which corresponds to repeated roots of a cubic equation is given explicitly, which is a new result. Our investigation demonstrates that complexity of a self-gravitating shear-free fluid is related to the existence of a first integral, and this may be extendable to general matter distributions.