bluuebunny/crossref_metadata_2025 huggingface dataset:
Porcine Interleukin-17 and 22 Co-Expressed by Yarrowia lipolytica Enhance Immunity and Increase Protection against Bacterial Challenge in Mice and Piglets
Authors: Peng Junjie , Yang Fang , Chen Jianlin , Guo Shaohua , Zhang Linhan , Deng Dinghao , Li Jiangling , Lv Xuebin , Gao Rong
Published: November 2022

Drug resistance in economic animals to pathogens is a matter of widespread concern due to abuse of antibiotics. In order to develop a safe and economical immunopotentiator to raise the immunity and antibacterial response as a replacement for antibiotics, a recombinant yeast co-expressing pig interleukin-17 (IL-17) and IL-22 was constructed and designated as Po1h-pINA1297-IL-17/22. To evaluate the immunoregulator activities of Po1h-pINA1297-IL-17/22, two experiment groups (oral inoculation with Po1h-pINA1297 or Po1h-pINA1297-IL-17/22) and a negative control group (PBS) were set up using 4-week-old female BALB/c mice (10/group). The level of cytokines, including IL-2, IL-4, IL-10, and IFN-γ, were detected by ELISA, and the circulating CD4+ and CD8+ lymphocytes were quantified by flow cytometry. The IgG and secretory IgA (SIgA) levels in both small intestine and fecal matter were also measured by ELISA. The results indicated that the IgG antibody titer and SIgA concentration increased significantly in the Po1h-pINA1297-IL17/22 group in comparison with the controls (p < 0.05) and so did the cytokine levels in the serum (IL-2, IL-4, IL-10, and IFN-γ). In addition, CD4+ and CD8+ T cells were also obviously elevated in the Po1h-pINA1297-IL17/22 group on 35th day (p < 0.05). After challenge with pathogenic Salmonella typhimurium, the Po1h-pINA1297-IL17/22 group showed a relatively higher survival rate without obvious infectious symptoms. On the contrary, the mortality of control group reached 80% due to bacterial infection. As for the piglet experiment, 30 healthy 7-day piglets were similarly attributed into three groups. The oral inoculation of piglets with Po1h-pINA1297-IL17/22 also markedly improved the growth performance and systemic immunity (up-regulations of IL-4, IL-6, IL-15, IL-17, IL-22, and IL-23). Overall, the results indicated that Po1h-pINA1297-IL17/22 effectively promoted the humoral and cellular immunity against bacterial infection. These proved the promising potential of Po1h-pINA1297-IL-17/22 to be a potent immunopotentiator for the prevention of microbial pathogen infections.
SNARE Modulators and SNARE Mimetic Peptides
Authors: Khvotchev Mikhail , Soloviev Mikhail
Published: November 2022

The soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) proteins play a central role in most forms of intracellular membrane trafficking, a key process that allows for membrane and biocargo shuffling between multiple compartments within the cell and extracellular environment. The structural organization of SNARE proteins is relatively simple, with several intrinsically disordered and folded elements (e.g., SNARE motif, N-terminal domain, transmembrane region) that interact with other SNAREs, SNARE-regulating proteins and biological membranes. In this review, we discuss recent advances in the development of functional peptides that can modify SNARE-binding interfaces and modulate SNARE function. The ability of the relatively short SNARE motif to assemble spontaneously into stable coiled coil tetrahelical bundles has inspired the development of reduced SNARE-mimetic systems that use peptides for biological membrane fusion and for making large supramolecular protein complexes. We evaluate two such systems, based on peptide-nucleic acids (PNAs) and coiled coil peptides. We also review how the self-assembly of SNARE motifs can be exploited to drive on-demand assembly of complex re-engineered polypeptides.
Substrate Type and Concentration Differently Affect Colon Cancer Cells Ultrastructural Morphology, EMT Markers, and Matrix Degrading Enzymes
Authors: Franchi Marco , Karamanos Konstantinos-Athanasios , Cappadone Concettina , Calonghi Natalia , Greco Nicola , Franchi Leonardo , Onisto Maurizio , Masola Valentina
Published: November 2022

Aim of the study was to understand the behavior of colon cancer LoVo-R cells (doxorubicin-resistant) vs. LoVo-S (doxorubicin sensitive) in the initial steps of extracellular matrix (ECM) invasion. We investigated how the matrix substrates Matrigel and type I collagen-mimicking the basement membrane (BM) and the normal or desmoplastic lamina propria, respectively-could affect the expression of epithelial-to-mesenchymal transition (EMT) markers, matrix-degrading enzymes, and phenotypes. Gene expression with RT-qPCR, E-cadherin protein expression using Western blot, and phenotypes using scanning electron microscopy (SEM) were analyzed. The type and different concentrations of matrix substrates differently affected colon cancer cells. In LoVo-S cells, the higher concentrated collagen, mimicking the desmoplastic lamina propria, strongly induced EMT, as also confirmed by the expression of Snail, metalloproteases (MMPs)-2, -9, -14 and heparanase (HPSE), as well as mesenchymal phenotypes. Stimulation in E-cadherin expression in LoVo-S groups suggests that these cells develop a hybrid EMT phenotype. Differently, LoVo-R cells did not increase their aggressiveness: no changes in EMT markers, matrix effectors, and phenotypes were evident. The low influence of ECM components in LoVo-R cells might be related to their intrinsic aggressiveness related to chemoresistance. These results improve understanding of the critical role of tumor microenvironment in colon cancer cell invasion, driving the development of new therapeutic approaches.
Galectin-3 and Myeloperoxidase May Monitor Cancer-Therapy-Related Cardiotoxicity? A Systematic Review and Meta-Analysis
Authors: Wu Yujuan , Gao Diansa , Xue Jinmin , Zuo Zhong
Published: November 2022

Galectin-3 and myeloperoxidase (MPO) are novel biomarkers in the field of cardio-oncology, but conflicting results have been reported. Hence, a meta-analysis was performed to assess the monitoring value of galectin-3 and MPO in cancer-therapy-related cardiotoxicity. PubMed, Cochrane, Web of Science, Embase, CNKI databases and ClinicalTrials.gov were queried. According to the predefined inclusion and exclusion criteria, eight studies with 1979 patients were included in this meta-analysis. The examination of the study’s heterogeneity (I2), quality assessment and statistical analysis were performed by two reviewers. No significant differences in galectin-3 levels were noted before and after treatment (WMD = −0.10, 90% CI −6.06–5.85, I2: 99%), and a weaker relationship was observed between galectin-3 evaluations and cancer-therapy-related cardiotoxicity (HR = 1.39, 90% CI 0.97–1.98, I2: 0%). However, MPO levels were increased in patients post-treatment (SMD = 0.58, 90% CI 0.35–0.80, I2: 56%), and an increased risk of cardiotoxicity was associated with early pre–post MPO assessments (HR = 1.16, 90% CI 1.02–1.32, I2: 21%). Surprisingly, the MPO levels were a more effective indicator of the response to tumor treatment compared with the TnI (SMD = 2.46, 90% CI −0.26–5.19, I2: 96%) and NT-proBNP levels (SMD = 1.08, 90% CI −0.82–2.98, I2: 96%). In conclusion, our meta-analysis suggests that MPO may rep-resent a potential biomarker for the early detection of cardiotoxicity in current cardio-oncology practice, but the monitoring value of galectin-3 requires further study.
A Large-Scale High-Throughput Screen for Modulators of SERCA Activity
Authors: Bidwell Philip A. , Yuen Samantha L. , Li Ji , Berg Kaja , Rebbeck Robyn T. , Aldrich Courtney C. , Roopnarine Osha , Cornea Razvan L. , Thomas David D.
Published: November 2022

The sarco/endoplasmic reticulum Ca-ATPase (SERCA) is a P-type ion pump that transports Ca2+ from the cytosol into the endoplasmic/sarcoplasmic reticulum (ER/SR) in most mammalian cells. It is critically important in muscle, facilitating relaxation and enabling subsequent contraction. Increasing SERCA expression or specific activity can alleviate muscle dysfunction, most notably in the heart, and we seek to develop small-molecule drug candidates that activate SERCA. Therefore, we adapted an NADH-coupled assay, measuring Ca-dependent ATPase activity of SERCA, to high-throughput screening (HTS) format, and screened a 46,000-compound library of diverse chemical scaffolds. This HTS platform yielded numerous hits that reproducibly alter SERCA Ca-ATPase activity, with few false positives. The top 19 activating hits were further tested for effects on both Ca-ATPase and Ca2+ transport, in both cardiac and skeletal SR. Nearly all hits increased Ca2+ uptake in both cardiac and skeletal SR, with some showing isoform specificity. Furthermore, dual analysis of both activities identified compounds with a range of effects on Ca2+-uptake and ATPase, which fit into distinct classifications. Further study will be needed to identify which classifications are best suited for therapeutic use. These results reinforce the need for robust secondary assays and criteria for selection of lead compounds, before undergoing HTS on a larger scale.
Heparan Sulfate Proteoglycans in Tauopathy
Authors: Zhu Yanan , Gandy Lauren , Zhang Fuming , Liu Jian , Wang Chunyu , Blair Laura J. , Linhardt Robert J. , Wang Lianchun
Published: November 2022

Tauopathies are a class of neurodegenerative diseases, including Alzheimer’s disease, and are characterized by intraneuronal tau inclusion in the brain and the patient’s cognitive decline with obscure pathogenesis. Heparan sulfate proteoglycans, a major type of extracellular matrix, have been believed to involve in tauopathies. The heparan sulfate proteoglycans co-deposit with tau in Alzheimer’s patient brain, directly bind to tau and modulate tau secretion, internalization, and aggregation. This review summarizes the current understanding of the functions and the modulated molecular pathways of heparan sulfate proteoglycans in tauopathies, as well as the implication of dysregulated heparan sulfate proteoglycan expression in tau pathology and the potential of targeting heparan sulfate proteoglycan-tau interaction as a novel therapeutic option.
Natural Sympathomimetic Drugs: From Pharmacology to Toxicology
Authors: Costa Vera Marisa , Grando Luciana Grazziotin Rossato , Milandri Elisa , Nardi Jessica , Teixeira Patrícia , Mladěnka Přemysl , Remião Fernando ,   on behalf of The OEMONOM
Published: November 2022

Sympathomimetic agents are a group of chemical compounds that are able to activate the sympathetic nervous system either directly via adrenergic receptors or indirectly by increasing endogenous catecholamine levels or mimicking their intracellular signaling pathways. Compounds from this group, both used therapeutically or abused, comprise endogenous catecholamines (such as adrenaline and noradrenaline), synthetic amines (e.g., isoproterenol and dobutamine), trace amines (e.g., tyramine, tryptamine, histamine and octopamine), illicit drugs (e.g., ephedrine, cathinone, and cocaine), or even caffeine and synephrine. In addition to the effects triggered by stimulation of the sympathetic system, the discovery of trace amine associated receptors (TAARs) in humans brought new insights about their sympathomimetic pharmacology and toxicology. Although synthetic sympathomimetic agents are mostly seen as toxic, natural sympathomimetic agents are considered more complacently in the terms of safety in the vision of the lay public. Here, we aim to discuss the pharmacological and mainly toxicological aspects related to sympathomimetic natural agents, in particular of trace amines, compounds derived from plants like ephedra and khat, and finally cocaine. The main purpose of this review is to give a scientific and updated view of those agents and serve as a reminder on the safety issues of natural sympathomimetic agents most used in the community.
Comparative Study of the Osteogenic Differentiation Potential of Adipose Tissue-Derived Stromal Cells and Dedifferentiated Adipose Cells of the Same Tissue Origin under Pro and Antioxidant Conditions
Authors: Bollmann Anne , Sons Hans Christian , Schiefer Jennifer Lynn , Fuchs Paul C. , Windolf Joachim , Suschek Christoph Viktor
Published: November 2022

Adipose tissue-derived stromal cells (ASCs) play an important role in various therapeutic approaches to bone regeneration. However, such applications become challenging when the obtained cells show a functional disorder, e.g., an impaired osteogenic differentiation potential (ODP). In addition to ASCs, human adipose tissue is also a source for another cell type with therapeutic potential, the dedifferentiated fat cells (DFATs), which can be obtained from mature adipocytes. Here, we for the first time compared the ODPs of each donors ASC and DFAT obtained from the same adipose tissue sample as well as the role of oxidative stress or antioxidative catalase on their osteogenic outcome. Osteogenic potential of ASC and DFAT from nine human donors were compared in vitro. Flow cytometry, staining for calcium accumulation with alizarin red, alkaline phosphatase assay and Western blots were used over an osteogenic induction period of up to 14 days. H2O2 was used to induce oxidative stress and catalase was used as an antioxidative measure. We have found that ASC and DFAT cultures’ ODPs are nearly identical. If ASCs from an adipose tissue sample showed good or bad ODP, so did the corresponding DFAT cultures. The inter-individual variability of the donor ODPs was immense with a maximum factor of about 20 and correlated neither with the age nor the sex of the donors of the adipose tissue. Oxidative stress in the form of exogenously added H2O2 led to a significant ODP decrease in both cell types, with this ODP decrease being significantly lower in DFAT cultures than in the corresponding ASC cultures. Regardless of the individual cell culture-specific ODP, however, exogenously applied catalase led to an approx. 2.5-fold increase in osteogenesis in the ASC and DFAT cultures. Catalase appears to be a potent pro-osteogenic factor, at least in vitro. A new finding that points to innovative strategies and therapeutic approaches in bone regeneration. Furthermore, our results show that DFATs behave similarly to ASCs of the same adipose tissue sample with respect to ODPs and could therefore be a very attractive and readily available source of multipotent stem cells in bone regenerative therapies.
Natural Compounds That Enhance Motor Function in a Mouse Model of Muscle Fatigue
Authors: Shibuya Shuichi , Watanabe Kenji , Sakuraba Daiki , Abe Takuya , Shimizu Takahiko
Published: November 2022

Musculoskeletal disease can be a serious condition associated with aging that may lead to fractures and a bedridden state due to decreased motor function. In addition to exercise training to increase muscle mass, increasing muscle function with the intake of functional foods is an effective treatment strategy for musculoskeletal disease. Muscle-specific SOD2-deficient mice (muscle-Sod2-/-) show a severe disturbance in exercise in association with increased mitochondrial reactive oxygen species, as well as mitochondrial dysfunction and muscle damage. In the present study, to develop a therapeutic strategy for musculoskeletal disease, we searched for substances that enhanced motor function among functional compounds by in vivo screening using muscle-Sod2-/- mice as a muscle fatigue model. We administered 96 compounds, including antioxidants, to muscle-Sod2-/- mice and assessed their effects on treadmill performance. Among the administered compounds, gossypin, genistein, kaempferol, taxifolin, fumaric acid, β-hydroxy-β-methylbutyrate Ca, and astaxanthin, which are dietary functional food factors, increased forced running time in muscle-Sod2-/- mice. In addition, troglitazone, tempol, trolox, and MnTE-2-PyP, which are antioxidants, also significantly increased the running ability of muscle-Sod2-/- mice. These results suggest that the intake of functional foods with antioxidant activity can improve motor function. Muscle-Sod2-/- mice, as a muscle fatigue model, are suitable for the in vivo screening of functional substances that promote improvements in exercise and muscle performance.
Comparative Analysis of Non-Coding RNA Transcriptomics in Heart Failure
Authors: Garcia-Padilla Carlos , Lozano-Velasco Estefanía , Garcia-Lopez Virginio , Aranega Amelia , Franco Diego , Garcia-Martinez Virginio , Lopez-Sanchez Carmen
Published: November 2022

Heart failure constitutes a clinical complex syndrome with different symptomatic characteristics depending on age, sex, race and ethnicity, among others, which has become a major public health issue with an increasing prevalence. One of the most interesting tools seeking to improve prevention, diagnosis, treatment and prognosis of this pathology has focused on finding new molecular biomarkers since heart failure relies on deficient cardiac homeostasis, which is regulated by a strict gene expression. Therefore, currently, analyses of non-coding RNA transcriptomics have been oriented towards human samples. The present review develops a comparative study emphasizing the relevance of microRNAs, long non-coding RNAs and circular RNAs as potential biomarkers in heart failure. Significantly, further studies in this field of research are fundamental to supporting their widespread clinical use. In this sense, the various methodologies used by the authors should be standardized, including larger cohorts, homogeneity of the samples and uniformity of the bioinformatic pipelines used to reach stratification and statistical significance of the results. These basic adjustments could provide promising steps to designing novel strategies for clinical management of patients with heart failure.
Macromolecules Absorbed from Influenza Infection-Based Sera Modulate the Cellular Uptake of Polymeric Nanoparticles
Authors: Nierenberg Daniel , Flores Orielyz , Fox David , Sip Yuen Yee Li , Finn Caroline M. , Ghozlan Heba , Cox Amanda , Coathup Melanie , McKinstry Karl Kai , Zhai Lei , Khaled Annette R.
Published: November 2022

Optimizing the biological identity of nanoparticles (NPs) for efficient tumor uptake remains challenging. The controlled formation of a protein corona on NPs through protein absorption from biofluids could favor a biological identity that enables tumor accumulation. To increase the diversity of proteins absorbed by NPs, sera derived from Influenza A virus (IAV)-infected mice were used to pre-coat NPs formed using a hyperbranched polyester polymer (HBPE-NPs). HBPE-NPs, encapsulating a tracking dye or cancer drug, were treated with sera from days 3–6 of IAV infection (VS3-6), and uptake of HBPE-NPs by breast cancer cells was examined. Cancer cells demonstrated better uptake of HBPE-NPs pre-treated with VS3-6 over polyethylene glycol (PEG)-HBPE-NPs, a standard NP surface modification. The uptake of VS5 pre-treated HBPE-NPs by monocytic cells (THP-1) was decreased over PEG-HBPE-NPs. VS5-treated HBPE-NPs delivered a cancer drug more efficiently and displayed better in vivo distribution over controls, remaining stable even after interacting with endothelial cells. Using a proteomics approach, proteins absorbed from sera-treated HBPE-NPs were identified, such as thrombospondin-1 (TSP-1), that could bind multiple cancer cell receptors. Our findings indicate that serum collected during an immune response to infection is a rich source of macromolecules that are absorbed by NPs and modulate their biological identity, achieving rationally designed uptake by targeted cell types.
States of Aggregation and Phase Transformation Behavior of Metallosurfactant Complexes by Hexacyanoferrate(II): Thermodynamic and Kinetic Investigation of ETR in Ionic Liquids and Liposome Vesicles
Authors: Nagaraj Karuppiah , Sakthinathan Subramanian , Chiu Te-Wei , Kamalesu Subramaniam , Lokhandwala Snehal , Parekh Nikhil M. , Karuppiah Chelladurai
Published: November 2022

Electronic absorption spectroscopy was used to study the ETR of surfactant–cobalt(III) complexes containing imidazo[4,5-f][1,10]phenanthroline, dipyrido[3,2-d:2′-3′-f]quinoxaline and dipyrido[3,2-a:2′,4′-c](6,7,8,9-tetrahydro)phenazine ligands by using ferrocyanide ions in unilamellar vesicles of dipalmitoylphosphotidylcholine (DPPC) and 1-butyl-3-methylimidazolium bromide ((BMIM)Br), at different temperatures under pseudo-first-order conditions using an excess of the reductant. The reactions were found to be second-order and the electron transfer is postulated as occurring in the outer sphere. The rate constant for the electron transfer reactions was found to increase with increasing concentrations of ionic liquids. Besides these, the effects of surfactant complex ions on liposome vesicles in these same reactions have also been studied on the basis of hydrophobicity. We observed that, below the phase transition temperature, there is an increasing amount of surfactant–cobalt(III) complexes expelled from the interior of the vesicle membrane through hydrophobic effects, while above the phase transition temperature, the surfactant–cobalt(III) complexes are expelled from the interior to the exterior surface of the vesicle. Kinetic data and activation parameters are interpreted in respect of an outer-sphere electron transfer mechanism. By assuming the existence of an outer-sphere mechanism, the results have been clarified based on the presence of hydrophobicity, and the size of the ligand increases from an ip to dpqc ligand and the reactants become oppositely charged. In all these media, the ΔS# values are recognized as negative in their direction in all the concentrations of complexes employed, indicative of a more ordered structure of the transition state. This is compatible with a model in which these complexes and [Fe(CN)6]4− ions bind to the DPPC in the transition state. Thus, the results have been interpreted based on the self-aggregation, hydrophobicity, charge densities of the co-ligand and the reactants with opposite charges.
A review of Optical Point-of-Care devices to Estimate the Technology Transfer of These Cutting-Edge Technologies
Authors: Pioz María Jesús , Espinosa Rocío L. , Laguna María Fe , Santamaria Beatriz , Murillo Ana María M. , Hueros Álvaro Lavín , Quintero Sergio , Tramarin Luca , Valle Luis G , Herreros Pedro , Bellido Alberto , Casquel Rafael , Holgado Miguel
Published: November 2022

Despite the remarkable development related to Point-of-Care devices based on optical technology, their difficulties when used outside of research laboratories are notable. In this sense, it would be interesting to ask ourselves what the degree of transferability of the research work to the market is, for example, by analysing the relation between the scientific work developed and the registered one, through patent. In this work, we provide an overview of the state-of-the-art in the sector of optical Point-of-Care devices, not only in the research area but also regarding their transfer to market. To this end, we explored a methodology for searching articles and patents to obtain an indicator that relates to both. This figure of merit to estimate this transfer is based on classifying the relevant research articles in the area and the patents that have been generated from these ones. To delimit the scope of this study, we researched the results of a large enough number of publications in the period from 2015 to 2020, by using keywords “biosensor”, “optic”, and “device” to obtain the most representative articles from Web of Science and Scopus. Then, we classified them according to a particular classification of the optical PoC devices. Once we had this sampling frame, we defined a patent search strategy to cross-link the article with a registered patent (by surfing Google Patents) and classified them accordingly to the categories described. Finally, we proposed a relative figure called Index of Technology Transference (IoTT), which estimates to what extent our findings in science materialized in published articles are protected by patent.
Paper-Based Biosensors for the Detection of Nucleic Acids from Pathogens
Authors: Wang Jiangshan , Davidson Josiah Levi , Kaur Simerdeep , Dextre Andres A. , Ranjbaran Mohsen , Kamel Mohamed S. , Athalye Shreya Milind , Verma Mohit S.
Published: November 2022

Paper-based biosensors are microfluidic analytical devices used for the detection of biochemical substances. The unique properties of paper-based biosensors, including low cost, portability, disposability, and ease of use, make them an excellent tool for point-of-care testing. Among all analyte detection methods, nucleic acid-based pathogen detection offers versatility due to the ease of nucleic acid synthesis. In a point-of-care testing context, the combination of nucleic acid detection and a paper-based platform allows for accurate detection. This review offers an overview of contemporary paper-based biosensors for detecting nucleic acids from pathogens. The methods and limitations of implementing an integrated portable paper-based platform are discussed. The review concludes with potential directions for future research in the development of paper-based biosensors.
Discriminant Criteria for Field Sexing in the Eurasian Tree Sparrow by Combining Body Size and Plumage Features
Authors: González Sergio , Morinha Francisco , Villanúa Diego , Goñi Lander , Blanco Guillermo
Published: November 2022

The Eurasian tree sparrow (Passer montanus) is a monomorphic passerine, for which it is impossible to differentiate between males and females based on external characteristics. Being a species frequently captured for ringing, having a reliable method to determine sex from conventional biometric measurements would facilitate its study and be very useful for the correct management and conservation of this declining species. In the present study, we used biometric measurements recorded in 66 individuals captured with mist nets in communal roosts in northern Spain during the winter and sexed them using molecular techniques. We conducted a discriminant function analysis (DFA) to derive equations that allowed us to determine the sex of the specimens from some of the measurements recorded in the field. Significant differences were found between males and females in wing length, third primary length, badge width and height and body weight. The DFA provided two functions that correctly classified the sex of 94.7% of the individuals using wing length and badge width, and 98.2% if weight was added to the analysis. Our results allow sexing from measurements that can be easily recorded in the field with the tools commonly used in banding sessions and without the need for additional training. Considerations of Bergmann’s and Allen’s rules on body size and the use of DFA in different populations are discussed.
Difference between the Effects of Peripheral Sensory Nerve Electrical Stimulation on the Excitability of the Primary Motor Cortex: Examination of the Combinations of Stimulus Frequency and Duration
Authors: Sato Masaaki , Mutai Hitoshi , Iwanami Jun , Noji Anna , Sugimoto Sayaka , Ozawa Kana , Sagari Akira
Published: November 2022

Peripheral sensory nerve electrical stimulation (PES) excites the primary motor cortex and is expected to improve motor dysfunction post-stroke. However, previous studies have reported a variety of stimulus frequencies and stimulus duration settings, and the effects of these different combinations on primary motor cortex excitability are not clear. We aimed to clarify the effects of different combinations of stimulus frequency and stimulus duration of PES on the excitation of primary motor cortex. Twenty-one healthy individuals (aged > 18 years, right-handed, and without a history of neurological or orthopedic disorders) were included. Each participant experienced three different stimulation frequencies (1, 10 and 50 Hz) and durations (20, 40 and 60 min). Motor-evoked potentials (MEPs) were recorded pre- and post-PES. The outcome measure was the change in primary motor cortex excitability using the MEP ratio. We used a D-optimal design of experiments and response surface analysis to define the optimal combination within nine different settings inducing more satisfying responses. The combination of stimulation frequency and stimulation time that maximized the desirability value was 10 Hz and 40 min, respectively. The results of this study may provide fundamental data for more minimally invasive and effective implementation of PES in patients with stroke.
Encephalocraniocutaneous Lipomatosis, a Radiological Challenge: Two Atypical Case Reports and Literature Review
Authors: Machnikowska-Sokołowska Magdalena , Fabrowicz Piotr , Pilch Jacek , Roesler Weronika , Kuźniak Mikołaj , Gruszczyńska Katarzyna , Paprocka Justyna
Published: November 2022

Encephalocraniocutaneous lipomatosis (ECCL; Haberland syndrome, #613001) is an extremely rare congenital disorder that is manifested by the involvement of the skin, eyes and central nervous system (CNS). We report two cases of children with ECCL diagnosis. First was an 8-year-old girl who presented with symptomatic epilepsy, cerebral palsy and developmental delay. In 2020, she was admitted to the hospital due to the exacerbation of paresis and intensified prolonged epileptic seizures, provoked by infection of the middle ear. Diagnostic imaging revealed radiological changes suggestive of ECCL, providing a reason for the diagnosis, despite the lack of skin and eye anomalies. The second child, a 14-year-old girl, was consulted for subtle clinical signs and epilepsy suspicion. Diagnostic imaging findings were similar, though less pronounced. Based on neuroradiological abnormalities typical for Haberland syndrome, the authors discuss possible ECCL diagnosis.
Research on the Sustainable Design of Commercial Street Space Based on Importance Performance Analysis
Authors: Hu Linhui , Yan Jiali , Zhu Yitong , Deng Junsen , Chen Lidan , Lu Shizhu
Published: November 2022

Street commerce is the basic unit of urban structure and an important part of people’s life. With the continuous advancement of online commerce, people’s consumption habits and consumption patterns have begun to change. (1) Background: During the epidemic, the global business environment changed dramatically, and traditional street business has also been hit hard, leaving a lot of idle space. The question is how to solve the problem of activating the commercial street space after its decay, and realize its sustainable development. (2) Methods: This paper takes the commercial space of Nonglin Street as the object, constructs the relevant factors affecting the commercial space of the street by using the theory of scenes, and collects the data by means of a field investigation and questionnaire. According to a weight analysis and satisfaction analysis, the advantages and disadvantages of the commerce in Nonglin Street are understood. (3) Results: The importance of the three variables of the appearance, comfort and diversity of the commercial space in Nonglin Street is very high and the satisfaction is low. (4) Conclusions: Nonglin Street need to increase diversified forms of business, open block space, integrate regional cultural symbols, and improve the management model of street commerce.
Point-of-Care Diagnosis of Endometrial Cancer Using the Surgical Intelligent Knife (iKnife)—A Prospective Pilot Study of Diagnostic Accuracy
Authors: Marcus Diana , Phelps David L. , Savage Adele , Balog Julia , Kudo Hiromi , Dina Roberto , Bodai Zsolt , Rosini Francesca , Ip Jacey , Amgheib Ala , Abda Julia , Manoli Eftychios , McKenzie James , Yazbek Joseph , Takats Zoltan , Ghaem-Maghami Sadaf
Published: November 2022

Introduction: Delays in the diagnosis and treatment of endometrial cancer negatively impact patient survival. The aim of this study was to establish whether rapid evaporative ionisation mass spectrometry using the iKnife can accurately distinguish between normal and malignant endometrial biopsy tissue samples in real time, enabling point-of-care (POC) diagnoses. Methods: Pipelle biopsy samples were obtained from consecutive women needing biopsies for clinical reasons. A Waters G2-XS Xevo Q-Tof mass spectrometer was used in conjunction with a modified handheld diathermy (collectively called the ‘iKnife’). Each tissue sample was processed with diathermy, and the resultant surgical aerosol containing ionic lipid species was then analysed, producing spectra. Principal component analyses and linear discriminant analyses were performed to determine variance in spectral signatures. Leave-one-patient-out cross-validation was used to test the diagnostic accuracy. Results: One hundred and fifty patients provided Pipelle biopsy samples (85 normal, 59 malignant, 4 hyperplasia and 2 insufficient), yielding 453 spectra. The iKnife differentiated between normal and malignant endometrial tissues on the basis of differential phospholipid spectra. Cross-validation revealed a diagnostic accuracy of 89% with sensitivity, specificity, positive predictive value and negative predictive value of 85%, 93%, 94% and 85%, respectively. Conclusions: This study is the first to use the iKnife to identify cancer in endometrial Pipelle biopsy samples. These results are highly encouraging and suggest that the iKnife could be used in the clinic to provide a POC diagnosis.
Interobserver Variability Prediction of Primary Gross Tumor in a Patient with Non-Small Cell Lung Cancer
Authors: Cheon Wonjoong , Jeong Seonghoon , Jeong Jong Hwi , Lim Young Kyung , Shin Dongho , Lee Se Byeong , Lee Doo Yeul , Lee Sung Uk , Suh Yang Gun , Moon Sung Ho , Kim Tae Hyun , Kim Haksoo
Published: November 2022

This research addresses the problem of interobserver variability (IOV), in which different oncologists manually delineate varying primary gross tumor volume (pGTV) contours, adding risk to targeted radiation treatments. Thus, a method of IOV reduction is urgently needed. Hypothesizing that the radiation oncologist’s IOV may shrink with the aid of IOV maps, we propose IOV prediction network (IOV-Net), a deep-learning model that uses the fuzzy membership function to produce high-quality maps based on computed tomography (CT) images. To test the prediction accuracy, a ground-truth pGTV IOV map was created using the manual contour delineations of radiation therapy structures provided by five expert oncologists. Then, we tasked IOV-Net with producing a map of its own. The mean squared error (prediction vs. ground truth) and its standard deviation were 0.0038 and 0.0005, respectively. To test the clinical feasibility of our method, CT images were divided into two groups, and oncologists from our institution created manual contours with and without IOV map guidance. The Dice similarity coefficient and Jaccard index increased by ~6 and 7%, respectively, and the Hausdorff distance decreased by 2.5 mm, indicating a statistically significant IOV reduction (p < 0.05). Hence, IOV-net and its resultant IOV maps have the potential to improve radiation therapy efficacy worldwide.
The Impact of COVID-19 Infection in Cancer 2020–2021
Authors: D’Orazi Gabriella , Cirone Mara
Published: November 2022

This Editorial summarizes the findings of the articles submitted in 2020 and 2021 to the Special Issue “The Impact of COVID-19 in Cancer”.
Incidence, Mortality and Survival Trends in Breast Cancers Coincident with Introduction of Mammography in the Nordic Countries
Authors: Hemminki Kari , Försti Asta
Published: November 2022

Survival in female breast cancers has generally improved but the relative contribution of early detection or treatment in this positive development is not known. Our aim was to assess the possible role of national mammography screening programs in survival improvement. Such screening has been offered to women, usually at 50–69 years of age, in Finland and Sweden since the 1980s and in Denmark and Norway since the 1990s. Participation rates have been high, ranging from 60% to 90%. We analyzed incidence and mortality changes and relative 5- and 10-year survival trends in breast cancer as novel measures in these countries using the NORDCAN database. Survival trends were compared in age groups of women who were screened to those who were not screened. We observed a relative survival advantage in 5-year and 10-year survival in the screened age groups after the period of national mammography screening was in place and this was consistent in each country. Timing and age-specific targeting of the improvements suggest that mammography may have contributed to the survival benefits. However, as we had no individual data on women who used the service, more detailed studies are needed to confirm the suggested survival advantage, particularly concerning mortality in stage-specific breast cancer.
Adrenomedullin Secreted by Melanoma Cells Promotes Melanoma Tumor Growth through Angiogenesis and Lymphangiogenesis
Authors: Benyahia Zohra , Gaudy-Marqueste Caroline , Berenguer-Daizé Caroline , Chabane Norhimane , Dussault Nadège , Cayol Mylène , Vellutini Christine , Djemli Amina , Nanni Isabelle , Beaufils Nathalie , Mabrouk Kamel , Grob Jean-Jacques , Ouafik L’Houcine
Published: November 2022

Introduction: Metastatic melanoma is an aggressive tumor and can constitute a real therapeutic challenge despite the significant progress achieved with targeted therapies and immunotherapies, thus highlighting the need for the identification of new therapeutic targets. Adrenomedullin (AM) is a peptide with significant expression in multiple types of tumors and is multifunctional. AM impacts angiogenesis and tumor growth and binds to calcitonin receptor-like receptor/receptor activity-modifying protein 2 or 3 (CLR/RAMP2; CLR/RAMP3). Methods: In vitro and in vivo studies were performed to determine the functional role of AM in melanoma growth and tumor-associated angiogenesis and lymphangiogenesis. Results: In this study, AM and AM receptors were immunohistochemically localized in the tumoral compartment of melanoma tissue, suggesting that the AM system plays a role in melanoma growth. We used A375, SK-MEL-28, and MeWo cells, for which we demonstrate an expression of AM and its receptors; hypoxia induces the expression of AM in melanoma cells. The proliferation of A375 and SK-MEL-28 cells is decreased by anti-AM antibody (αAM) and anti-AMR antibodies (αAMR), supporting the fact that AM may function as a potent autocrine/paracrine growth factor for melanoma cells. Furthermore, migration and invasion of melanoma cells increased after treatment with AM and decreased after treatment with αAMR, thus indicating that melanoma cells are regulated by AM. Systemic administration of αAMR reduced neovascularization of in vivo Matrigel plugs containing melanoma cells, as demonstrated by reduced numbers of vessel structures, which suggests that AM is one of the melanoma cells-derived factors responsible for endothelial cell-like and pericyte recruitment in the construction of neovascularization. In vivo, αAMR therapy blocked angiogenesis and lymphangiogenesis and decreased proliferation in MeWo xenografts, thereby resulting in tumor regression. Histological examination of αAMR-treated tumors showed evidence of the disruption of tumor vascularity, with depletion of vascular endothelial cells and a significant decrease in lymphatic endothelial cells. Conclusions: The expression of AM by melanoma cells promotes tumor growth and neovascularization by supplying/amplifying signals for neoangiogenesis and lymphangiogenesis.
Regulation of Metabolic Plasticity in Cancer Stem Cells and Implications in Cancer Therapy
Authors: Papadaki Styliani , Magklara Angeliki
Published: November 2022

Cancer stem cells (CSCs), a subpopulation of tumor cells with self-renewal capacity, have been associated with tumor initiation, progression, and therapy resistance. While the bulk of tumor cells mainly use glycolysis for energy production, CSCs have gained attention for their ability to switch between glycolysis and oxidative phosphorylation, depending on their energy needs and stimuli from their microenvironment. This metabolic plasticity is mediated by signaling pathways that are also implicated in the regulation of CSC properties, such as the Wnt/β-catenin, Notch, and Hippo networks. Two other stemness-associated processes, autophagy and hypoxia, seem to play a role in the metabolic switching of CSCs as well. Importantly, accumulating evidence has linked the metabolic plasticity of CSCs to their increased resistance to treatment. In this review, we summarize the metabolic signatures of CSCs and the pathways that regulate them; we especially highlight research data that demonstrate the metabolic adaptability of these cells and their role in stemness and therapy resistance. As the development of drug resistance is a major challenge for successful cancer treatment, the potential of specific elimination of CSCs through targeting their metabolism is of great interest and it is particularly examined.
Management and Prognosis of Cardiac Metastatic Merkel Cell Carcinoma: A Case–Control Study and Literature Review
Authors: Akaike Tomoko , Cahill Kelsey , Akaike Gensuke , Huynh Emily T. , Hippe Daniel S. , Shinohara Michi M. , Liao Jay , Apisarnthanarax Smith , Parvathaneni Upendra , Hall Evan , Bhatia Shailender , Cheng Richard K. , Nghiem Paul , Tseng Yolanda D.
Published: November 2022

Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin cancer, has a high rate (20%) of distant metastasis. Within a prospective registry of 582 patients with metastatic MCC (mMCC) diagnosed between 2003–2021, we identified 9 (1.5%) patients who developed cardiac metastatic MCC (mMCC). We compared overall survival (OS) between patients with cardiac and non-cardiac metastases in a matched case–control study. Cardiac metastasis was a late event (median 925 days from initial MCC diagnosis). The right heart was predominantly involved (8 of 9; 89%). Among 7 patients treated with immunotherapy, 6 achieved a complete or partial response of the cardiac lesion. Among these 6 responders, 5 received concurrent cardiac radiotherapy (median 20 Gray) with immunotherapy; 4 of 5 did not have local disease progression or recurrence in the treated cardiac lesion. One-year OS was 44%, which was not significantly different from non-cardiac mMCC patients (45%, p = 0.96). Though it occurs relatively late in the disease course, cardiac mMCC responded to immunotherapy and/or radiotherapy and was not associated with worse prognosis compared to mMCC at other anatomic sites. These results are timely as cardiac mMCC may be increasingly encountered in the era of immunotherapy as patients with metastatic MCC live longer.
Impact of Systemic Autoimmune Diseases on Treatment Outcomes and Radiation Toxicities in Patients with Stage I Non-Small Cell Lung Cancer Receiving Stereotactic Body Radiation Therapy: A Matched Case-Control Analysis
Authors: Chen Zhe , Nonaka Hotaka , Onishi Hiroshi , Nakatani Eiji , Oguri Mitsuhiko , Saito Masahide , Aoki Shinichi , Marino Kan , Komiyama Takafumi , Kuriyama Kengo , Araya Masayuki , Tominaga Licht , Saito Ryo , Maehata Yoshiyasu , Shinohara Ryoji
Published: November 2022

We aimed to evaluate the impact of systemic autoimmune diseases (SADs) on treatment outcomes and radiation toxicities following stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC). We queried an institution-based database on patients with SADs treated with SBRT for lung cancer between 2001 and 2016 (SAD group). Each patient was matched to three controls without SADs. The primary outcomes of interest were the overall survival (OS) and local control rate (LCR). The secondary outcomes were radiation toxicities of grades ≥2 (≥G2). Twelve patients with SADs were matched to 36 controls. The median follow-up duration was 3.6 years. There was a significant intergroup difference in the OS (hazard ratio [HR]: 4.11, 95% confidence incidence [CI]: 1.82–9.27, p < 0.001) and LCR (HR: 15.97, 95% CI: 2.89–88.29, p < 0.001). However, there were no significant intergroup differences in the odds of acute (odds ratio [OR]: 0.38, 95% CI: 0.02–8.91, p = 0.550) and late (OR: 2.20, 95% CI: 0.32–15.10, p = 0.422) ≥G2 radiation pneumonitis. No other ≥G2 toxicities were identified. In conclusion, although radiation toxicities are not enhanced by SADs, SADs are risk factors of poor prognosis following SBRT for stage I NSCLC.
Targeting FTO Suppresses Pancreatic Carcinogenesis via Regulating Stem Cell Maintenance and EMT Pathway
Authors: Garg Rachana , Melstrom Laleh , Chen Jianjun , He Chuan , Goel Ajay
Published: November 2022

N6-methyladenosine (m6A) is the most prevalent post-transcriptional RNA modification regulating cancer self-renewal. However, despite its functional importance and prognostic implication in tumorigenesis, the relevance of FTO, an m6A eraser, in pancreatic cancer (PC) remains elusive. Here, we establish the oncogenic role played by FTO overexpression in PC. FTO is upregulated in PC cells compared to normal human pancreatic ductal epithelial (HPDE) cells. Both RNAi depletion and CS1-mediated pharmacological inhibition of FTO caused a diminution of PC cell proliferation via cell cycle arrest in the G1 phase and p21cip1 and p27kip1 induction. While HPDE cells remain insensitive to CS1 treatment, FTO overexpression confers enhancements in growth, motility, and EMT transition, thereby inculcating tumorigenic properties in HPDE cells. Notably, shRNA-mediated FTO depletion in PC cells impairs their mobility and invasiveness, leading to EMT reversal. Mechanistically, this was associated with impaired tumorsphere formation and reduced expression of CSCs markers. Furthermore, FTO depletion in PC cells weakened their tumor-forming capabilities in nude mice; those tumors had increased apoptosis, decreased proliferation markers, and MET conversion. Collectively, our study demonstrates the functional importance of FTO in PC and the maintenance of CSCs via EMT regulation. Thus, FTO may represent an attractive therapeutic target for PC.
Secondary Malignancies after Ewing Sarcoma—Epidemiological and Clinical Analysis of an International Trial Registry
Authors: Kaiser Isabelle , Kauertz Katja , Zöllner Stefan K. , Hartmann Wolfgang , Langer Thorsten , Jürgens Heribert , Ranft Andreas , Dirksen Uta
Published: November 2022

Ewing sarcoma (EwS) represents highly aggressive bone and soft tissue tumors that require intensive treatment by multi-chemotherapy, surgery and/or radiotherapy. While therapeutic regimens have increased survival rates, EwS survivors face long-term sequelae that include secondary malignant neoplasms (SMNs). Consequently, more knowledge about EwS patients who develop SMNs is needed to identify high-risk patients and adjust follow-up strategies. We retrospectively analyzed data from 4518 EwS patients treated in five consecutive EwS trials from the Cooperative Ewing Sarcoma Study (CESS) group. Ninety-six patients developed SMNs after primary EwS, including 53 (55.2%) with solid tumors. The latency period between EwS and the first SMN was significantly longer for the development of solid SMNs (median: 8.4 years) than for hematologic SMNs (median: 2.4 years) (p < 0.001). The cumulative incidence (CI) of SMNs in general increased over time from 0.04 at 10 years to 0.14 at 30 years; notably, the specific CI for hematologic SMNs remained stable over the different decades, whereas for solid SMNs it gradually increased over time and was higher for metastatic patients than in localized EwS patients (20 years: 0.14 vs. 0.06; p < 0.01). The clinical characteristics of primary EwS did not differ between patients with or without SMNs. All EwS patients received multi-chemotherapy with adjuvant radiotherapy in 77 of 96 (80.2%) patients, and the use of radiation doses ≥ 60 Gy correlated with the occurrence of SMNs. The survival rate after SMNs was 0.49, with a significantly better outcome for solid SMNs compared with hematologic SMNs (3 years: 0.70 vs. 0.24, respectively; p < 0.001). The occurrence of SMNs after EwS remains a rare event but requires a structured follow-up system because it is associated with high morbidity and mortality.