bluuebunny/crossref_metadata_2025 huggingface dataset:
Response Analysis of Asymmetric Monostable Harvesters Driven by Color Noise and Band-Limited Noise
Authors: Liu Shuangyan , Wang Wei
Published: October 2021

In this paper, we investigate the response of asymmetric potential monostable energy harvesters (MEHs) excited by color noise and band-limited noise. The motivation for this study is that environmental vibrations always have the characteristic of randomness, and it is difficult to modulate a perfectly symmetric MEH. For the excitation of exponentially correlated color noise, the moment differential equation was applied to evaluate the output performance of the asymmetric potential MEHs. Numerical and theoretical analyses were carried out to investigate the influence of noise intensity and internal system parameters on the output power of the system. Our results demonstrate that the output performance of the asymmetric MEH decreases with the increase in the correlation time, which determines the character of the color noise. On the contrary, the increase in the asymmetric degree enhances the output power of the asymmetric MEH subjected to color noise. For the band-limited noise excitation, numerical simulation is undertaken to consider the response of the asymmetric MEHs, and outcomes indicate that the frequency bandwidth and center frequency have a significant influence on the output performance. Regarding the asymmetric potential, its appearance leads the MEHs to generate higher output power at lower frequencies and this phenomenon is more obvious with the increase in the degree of asymmetry. Finally, we observed that the characteristics of the response bandwidth of asymmetric MEHs subjected to band-limited noise excitation are similar to the response under harmonic excitation.
Intercomparisons of Tropospheric Wind Velocities Measured by Multi-Frequency Wind Profilers and Rawinsonde
Authors: Chen Zhao-Yu , Chu Yen-Hsyang , Su Ching-Lun
Published: October 2021

Concurrent measurements of three-dimensional wind velocities made with three co-located wind profilers operated at frequencies of 52 MHz, 449 MHz, and 1.29 GHz for the period 12–16 September 2017 are compared for the first time in this study. The velocity–azimuth display (VAD) method is employed to estimate the wind velocities. The result shows that, in the absence of precipitation, the root mean square difference (RMSD) in the horizontal wind speed velocities U and wind directions D between different pairs of wind profilers are, respectively, in the range of 0.94–0.99 ms−1 and 7.7–8.3°, and those of zonal wind component u and meridional wind component v are in the respective ranges of 0.91–1.02 ms−1 and 1.1–1.24 ms−1. However, the RMSDs between wind profilers and rawinsonde are in the range of 2.89–3.26 ms−1 for horizontal wind speed velocity and 11.17–14.48° for the wind direction, which are around 2–3 factors greater than those between the wind profilers on average. In addition to the RMSDs, MDs between wind profilers and radiosonde are around one order of magnitude larger than those between wind profilers. These results show that the RMSDs, MDs, and Stdds between radars are highly consistent with each other, and they are much smaller than those between radar and rawinsonde. This therefore suggests that the wind profiler-measured horizontal wind velocities are much more reliable, precise, and accurate than the rawinsonde measurement.
Structure and Evolution of Non-Lake-Effect Snow Producing Alberta Clippers
Authors: Wiley Jake , Mercer Andrew
Published: October 2021

Alberta Clippers (clippers) have long been associated with lake-effect snow (LES) events due to their frequent passage over the Great Lakes basin. However, not all clippers produce LES, and no research has inquired into which synoptic fields most influence LES formation. This study analyzes clippers during non-LES situations to further knowledge on which atmospheric variables most regulate LES development on the synoptic scale. As no such database currently exists, a clipper repository is developed using National Centers for Environmental Prediction Reanalysis data. The repository is then cross referenced with a previously developed LES repository to identify clippers responsible for LES. Composite synoptic-scale patterns were then constructed on the remaining non-LES clippers to identify synoptic conditions that ultimately inhibited LES formation. This analysis is supplemented by an assessment of lake surface conditions in each composite to evaluate how influential the lake characteristics were in the suppression of LES activity. In total, 51 non-LES clippers were identified, tracked, and separated into three composite map types that exhibited unique storm track and spatial characteristics. Permutation testing revealed that lake surface conditions were not significantly (p ≤ 0.05) different between LES and non-LES associated clippers implying the main LES inhibition factors were meteorological.
Environmental Odour
Authors: Schauberger Günther , Piringer Martin , Wu Chuandong , Koziel Jacek A.
Published: October 2021

Environmental odour is perceived as a major nuisance by the rural and urban population [...]
Metabolomic Studies for Metabolic Alterations Induced by Non-Steroidal Anti-Inflammatory Drugs: Mini Review
Authors: Ghosh Soumita
Published: October 2021

Non-steroidal anti-inflammatory drugs (NSAIDs) are Food and Drug Administration (FDA) approved antipyretic, anti-inflammatory, and analgesic drugs to mitigate pain, however it is associated with gastrointestinal injury and cardiovascular disease in some individuals. Metabolomics has the potential to understand the interaction of host and the drugs, such as NSAIDs administration. This discipline has been used by many researchers to understand the serious side effects of NSAIDs. We highlighted (1) the potential of metabolomics in understanding the pathogenesis of adverse events due to NSAIDs administration; (2) choice of metabolomics techniques, bio sample handling; (3) review of metabolomics studies in the front of NSAIDs in different biofluids and tissues; (4) pathway analysis of the data presented in the published literature. In our analysis we find tricarboxylic acid cycle (TCA), “glycine serine and threonine metabolism,” “alanine, aspartate, and glutamate metabolism,” and fatty acid metabolism to be altered by the NSAIDs like ibuprofen, indomethacin, naproxen, aspirin, and celecoxib. In conclusion, metabolomics allows the use of biological samples to identify useful pathways involved in disease progression, and subsequently inform a greater understanding of the disease pathogenesis. A further in-depth investigation of the associated pathways mentioned above holds the potential for drug targets for side effects mitigation.
The Self and Its Right Insula—Differential Topography and Dynamic of Right vs. Left Insula
Authors: Scalabrini Andrea , Wolman Angelika , Northoff Georg
Published: October 2021

Various studies demonstrate a special role of the right compared to the left anterior insula in mediating our self. However, the neural features of the right insula that allow for its special role remain unclear. Presupposing a spatiotemporal model of self—“Basis model of self-specificity” (BMSS)—we here address the following question: what spatial-topographic and temporal-dynamic features render neural activity in the right insula to be more suitable in mediating self-specificity than the left insula? First, applying fMRI, we demonstrate that the right insula (i) exhibits higher degrees of centrality in rest, and (ii) higher context-dependent functional connectivity in a self-specific task among regions of distinct layers of self (intero-, extero-proprioceptive, and mental). Second, using EEG in rest and task, we show that the right insula shows longer autocorrelation window (ACW) in its neural activity than both left insula and other regions of the different layers of self. Together, we demonstrate special topographic, i.e., high functional connectivity, and dynamic, i.e., long ACW, neural features of the right insula compared to both left insula and other regions of the distinct layers of self. This suits neural activity in the right insula ideally for high functional integration and temporal continuity as key features of the self including its intero-, extero-proprioceptive, and mental layers.
Foreign Language Training to Stimulate Cognitive Functions
Authors: Herrera Naranjo Sol , Suárez de la Torre Mercedes , Restrepo de Mejía Francia , Facal David
Published: October 2021

Adult development throughout a lifetime implies a series of changes in systems, including cognitive and linguistic functioning. The aim of this article is to study the effect of foreign language training on linguistic processing, particularly the frequency of the tip-of-the-tongue (TOT) phenomenon and on other cognitive processes such as processing speed and working memory in adults aged 40 to 60 years. Sixty-six healthy Colombian teachers were enrolled in this study. They were then randomly divided into an experimental group (33 healthy adults who underwent a four-week training period) and a passive control group (33 healthy adults who did not undergo any training). All participants performed induction tasks for the TOT phenomenon, working memory and processing speed before and after the four weeks. Results showed more of an effect in the semantic access, phonological access and processing speed measures with a better performance in the experimental group than in the control group. In Colombia, this type of training is still new and little is known to date about programs to prevent cognitive impairments. The need to conduct more studies confirming or refuting these findings is discussed, thus raising awareness about the extent of this type of training to increase the linguistic and cognitive performance of adults.
Near-Infrared MAO A Inhibitor (NMI) Outperformed FDA-Approved Chemotherapeutic Agents in Brain and Other Cancers: A Bioinformatic Analysis of NCI60 Screening Data
Authors: Feng Qianhua , Lian Yuxuan , Qian Yihan , Shih Jean C.
Published: October 2021

Our previous work has shown that monoamine oxidase A (MAO A) is overexpressed in glioma and prostate cancer. Near-infrared dye conjugate MAO A Inhibitor (NMI) inhibited the growth of these cancers. This study investigated the effects of NMI on other cancers by NCI60 screening. Our results showed that 48 out of 59 screened cell lines from nine types of cancer had 100% growth inhibition at 10 μM NMI treatment. The in vitro efficacy of NMI determined by growth inhibition (GI50 and TGI) and lethal doses (LC50) has been further studied in various cell lines of CNS cancer, prostate cancer, and non-small cell lung cancer (NSCLC), these three cancers showed increased MAO A expression in tumors compared to normal tissues. Based on the waterfall plots and the 3D scatter plot of GI50, TGI, and LC50 data, NMI showed higher potency to several CNS cancer and NSCLC cell lines than prostate cancer cell lines. In vitro efficacy of NMI outperformed FDA-approved drugs for CNS cancer, prostate cancer, and NSCLC, respectively. The Pairwise Pearson Correlation Coefficient (PCC) showed that NMI has a unique mechanism compared to the existing anticancer drugs. This study shows that NMI is a novel theragnostic drug with high potency and unique mechanisms for brain, prostate, NSCLC, and other cancers.
Experimental Study on Engineering Properties of Cement Concrete Reinforced with Nylon and Jute Fibers
Authors: Bheel Naraindas , Tafsirojjaman T. , Liu Yue , Awoyera Paul , Kumar Aneel , Keerio Manthar Ali
Published: October 2021

The use of synthetic fiber and natural fiber for concrete production has been continuously investigated. Most of the materials have become popular for their higher flexibility, durability, and strength. However, the current study explores the engineering properties of cement concrete reinforced with nylon and jute fibers together. Varying proportions and lengths of nylon and jute fibers were utilized in the concrete mixture. Hence, the combined effects of nylon and jute fibers on workability, density, water absorption, compressive, tensile, flexural strength, and drying shrinkage of concrete were investigated. Results showed that concrete with 1% of nylon and jute fibers together by the volume fraction showed a maximum enhancement of the compressive strength, split tensile strength, and flexural strength by 11.71%, 14.10%, and 11.04%, respectively, compared to the control mix of concrete at 90 days. However, the water absorption of concrete increased with increasing nylon and jute fiber contents. The drying shrinkage of concrete decreased with the addition of nylon and jute fibers together after 90 days. Thus, the sparing application of both nylon and jute fiber as discussed in this study can be adopted for concrete production.
Imaging of Skull Base and Orbital Invasion in Sinonasal Cancer: Correlation with Histopathology
Authors: Salfrant Maxime , Garcia Gabriel C. T. E. , Guichard Jean-Pierre , Bidault François , Reizine Daniel , Aupérin Anne , Bresson Damien , Verillaud Benjamin , Herman Philippe , Moya-Plana Antoine
Published: October 2021

Background: Pretreatment assessment of local extension in sinonasal cancer is essential for prognostic evaluation and surgical planning. The aim of this study was to assess the diagnostic performance of two common imaging techniques (CT and MRI) for the diagnosis of skull base and orbital invasion by comparing imaging findings to histopathological data. Methods: This was a retrospective two-center study including patients with sinonasal cancer involving the skull base and/or the orbit operated on between 2000 and 2019. Patients were included only if pre-operative CT and/or MRI, operative and histopathologic reports were available. A double prospective blinded imaging review was conducted according to predefined radiological parameters. Radiologic tumor extension was compared to histopathological reports, which were considered the gold standard. The predictive positive value (PPV) for the diagnosis of skull base/orbital invasion was calculated for each parameter. Results: A total of 176 patients were included. Ethmoidal intestinal-type adenocarcinoma was the most common type of cancer (41%). The PPV for major modification of the bony skull base was 78% on the CT scan, and 89% on MRI. MRI signs of dural invasion with the highest PPVs were: contact angle over 45° between tumor and dura (86%), irregular deformation of dura adjacent to tumor (87%) and nodular dural enhancement over 2 mm in thickness (87%). Signs of orbital invasion had low PPVs (<50%). Conclusions: This retrospective study provides objective data about the diagnostic value of pretreatment imaging in patients with sinonasal cancer.
Relationship between Circulating Lipids and Cytokines in Metastatic Castration-Resistant Prostate Cancer
Authors: Lin Hui-Ming , Yeung Nicole , Hastings Jordan F. , Croucher David R. , Huynh Kevin , Meikle Thomas G. , Mellett Natalie A. , Kwan Edmond M. , Davis Ian D. , Tran Ben , Mahon Kate L. , Zhang Alison , Stockler Martin R. , Briscoe Karen , Marx Gavin , Bastick Patricia , Crumbaker Megan L. , Joshua Anthony M. , Azad Arun A. , Meikle Peter J. , Horvath Lisa G.
Published: October 2021

Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions.
Promising Epigenetic Biomarkers for the Early Detection of Colorectal Cancer: A Systematic Review
Authors: Anghel Sorina Andreea , Ioniță-Mîndrican Corina-Bianca , Luca Ioana , Pop Anca Lucia
Published: October 2021

In CRC, screening compliance is decreased due to the experienced discomfort associated with colonoscopy, although this method is the gold standard in terms of sensitivity and specificity. Promoter DNA methylation (hypomethylation or hypermethylation) has been linked to all CRC stages. Study objectives: to systematically review the current knowledge on approved biomarkers, reveal new potential ones, and inspect tactics that can improve performance. This research was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines; the risk of bias was evaluated using the revised Quality Assessment of Diagnostic Accuracy Studies criteria (QUADAS-2). The Web of Science® Core Collection, MEDLINE® and Scopus® databases were searched for original articles published in peer-reviewed journals with the specific keywords “colorectal cancer”, “early detection”, “early-stage colorectal cancer”, “epigenetics”, “biomarkers”, “DNA methylation biomarkers”, “stool or blood or tissue or biopsy”, “NDRG4”, “BMP3”, “SEPT9”, and “SDC2”. Based on eligibility criteria, 74 articles were accepted for analysis. mSDC2 and mSEPT9 were frequently assessed in studies, alone or together as part of the ColoDefense panel test—the latter with the greatest performance. mBMP3 may not be an appropriate marker for detecting CRC. A panel of five methylated binding sites of the CTCF gene holds the promise for early-stage specific detection of CRC. CRC screening compliance and accuracy can be enhanced by employing a stool mt-DNA methylation test.
CD44v6 Defines a New Population of Circulating Tumor Cells Not Expressing EpCAM
Authors: Belthier Guillaume , Homayed Zeinab , Grillet Fanny , Duperray Christophe , Vendrell Julie , Krol Ilona , Bravo Sophie , Boyer Jean-Christophe , Villeronce Olivia , Vitre-Boubaker Jihane , Heaug-Wane Diana , Macari-Fine Françoise , Smith Jai , Merlot Matthieu , Lossaint Gérald , Mazard Thibault , Portales Fabienne , Solassol Jérôme , Ychou Marc , Aceto Nicola , Mamessier Emilie , Bertucci François , Pascussi Jean Marc , Samalin Emmanuelle , Hollande Frédéric , Pannequin Julie
Published: October 2021

Circulating tumor cells (CTCs) are promising diagnostic and prognostic tools for clinical use. In several cancers, including colorectal and breast, the CTC load has been associated with a therapeutic response as well as progression-free and overall survival. However, counting and isolating CTCs remains sub-optimal because they are currently largely identified by epithelial markers such as EpCAM. New, complementary CTC surface markers are therefore urgently needed. We previously demonstrated that a splice variant of CD44, CD44 variable alternative exon 6 (CD44v6), is highly and specifically expressed by CTC cell lines derived from blood samples in colorectal cancer (CRC) patients. Two different approaches—immune detection coupled with magnetic beads and fluorescence-activated cell sorting—were optimized to purify CTCs from patient blood samples based on high expressions of CD44v6. We revealed the potential of the CD44v6 as a complementary marker to EpCAM to detect and purify CTCs in colorectal cancer blood samples. Furthermore, this marker is not restricted to colorectal cancer since CD44v6 is also expressed on CTCs from breast cancer patients. Overall, these results strongly suggest that CD44v6 could be useful to enumerate and purify CTCs from cancers of different origins, paving the way to more efficacious combined markers that encompass CTC heterogeneity.
An Epigenetic Perspective on Intra-Tumour Heterogeneity: Novel Insights and New Challenges from Multiple Fields
Authors: Beyes Sven , Bediaga Naiara Garcia , Zippo Alessio
Published: October 2021

Cancer is a group of heterogeneous diseases that results from the occurrence of genetic alterations combined with epigenetic changes and environmental stimuli that increase cancer cell plasticity. Indeed, multiple cancer cell populations coexist within the same tumour, favouring cancer progression and metastatic dissemination as well as drug resistance, thereby representing a major obstacle for treatment. Epigenetic changes contribute to the onset of intra-tumour heterogeneity (ITH) as they facilitate cell adaptation to perturbation of the tumour microenvironment. Despite being its central role, the intrinsic multi-layered and reversible epigenetic pattern limits the possibility to uniquely determine its contribution to ITH. In this review, we first describe the major epigenetic mechanisms involved in tumourigenesis and then discuss how single-cell-based approaches contribute to dissecting the key role of epigenetic changes in tumour heterogeneity. Furthermore, we highlight the importance of dissecting the interplay between genetics, epigenetics, and tumour microenvironments to decipher the molecular mechanisms governing tumour progression and drug resistance.
Partial Versus Total Omentectomy in Patients with Gastric Cancer: A Systemic Review and Meta-Analysis
Authors: Chai Shion Wei , Wang Suo-Hsien , Wang Chih-Yuan , Chen Yi-Chan , Soong Ruey-Shyang , Huang Ting-Shuo
Published: October 2021

Background: Surgical treatment is the key to cure localized gastric cancer. There is no strong evidence that supports the value of omentectomy. Thus, a meta-analysis was conducted to compare the safety and efficiency of partial and total omentectomy in patients with gastric cancer. Methods: PubMed, Embase, and Cochrane Library databases were searched. All studies that compared total and partial omentectomy as treatments for gastric cancer were included. The primary outcomes were patients’ overall survival and disease-free survival, while the secondary outcomes were perioperative outcome and postoperative complications. Results: A total of nine studies were examined, wherein 1043 patients were included in the partial omentectomy group, and 1995 in the total omentectomy group. The partial omentectomy group was associated with better overall survival (hazard ratio: 0.80, 95% CI: 0.66 to 0.98, p = 0.04, I2 = 0%), shorter operative time, and lesser blood loss than the total omentectomy group. In addition, no statistically significant difference was observed in the number of dissected lymph nodes, length of hospital stays, complication rate, and disease-free survival. Conclusions: Our results show that, compared with total omentectomy in gastric cancer surgery, partial omentectomy had non-inferior oncological outcomes and comparable safety outcomes.
Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy
Authors: Karpova Yaroslava , Guo Danping , Makhov Peter , Haines Adam , Markov Dmitriy , Kolenko Vladimir , Tulin Alexei
Published: October 2021

Poly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have shown that the development of clear cell renal cell carcinoma (ccRCC) is associated with extreme accumulation of pADPr caused by the enhanced expression of PARP-1 and decreased PARG levels. The most severe misregulation of pADPr turnover is found in ccRCC specimens from metastatic lesions. Both, classical NAD-like and non-NAD-like PARP-1 inhibitors reduced viability and clonogenic potential of ccRCC cell lines and suppressed growth of ccRCC xenograft tumors. However, classical NAD-like PARP-1 inhibitors affected viability of normal kidney epithelial cells at high concentrations, while novel non-NAD-like PARP-1 inhibitors exhibited activity against malignant cells only. We have also utilized different approaches to reduce the pADPr level in ccRCC cells by stably overexpressing PARG and demonstrated the prominent antitumor effect of this “back-to-normal” intervention. We also generated ccRCC cell lines with stable overexpression of PARG under doxycycline induction. This genetic approach demonstrated significantly affected malignancy of ccRCC cells. Transcriptome analysis linked observed phenotype with changes in gene expression levels for lipid metabolism, interferon signaling, and angiogenesis pathways along with the changes in expression of key cancer-related genes.
The Diverse Applications of Pancreatic Ductal Adenocarcinoma Organoids
Authors: Low Ronnie Ren Jie , Lim Wei Wen , Nguyen Paul M. , Lee Belinda , Christie Michael , Burgess Antony W. , Gibbs Peter , Grimmond Sean M. , Hollande Frédéric , Putoczki Tracy L.
Published: October 2021

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies. While immortalized cancer cell lines and genetically engineered murine models have increased our understanding of PDAC tumorigenesis, they do not recapitulate inter- and intra-patient heterogeneity. PDAC patient derived organoid (PDO) biobanks have overcome this hurdle, and provide an opportunity for the high throughput screening of potential new therapies. This review provides a summary of the PDAC PDO biobanks established to date, and discusses how they have advanced our understanding of PDAC biology. Looking forward, the development of coculturing techniques for specific immune or stromal cell populations will enable a better understanding of the crosstalk that occurs within the tumor microenvironment, and the impact of this crosstalk on treatment response.
Gut Microbiota-Related Cellular and Molecular Mechanisms in the Progression of Nonalcoholic Fatty Liver Disease
Authors: Park Eunju , Jeong Jin-Ju , Won Sung-Min , Sharma Satya Priya , Gebru Yoseph Asmelash , Ganesan Raja , Gupta Haripriya , Suk Ki Tae , Kim Dong Joon
Published: October 2021

Nonalcoholic fatty liver disease (NAFLD) is one of the most common and increasing liver diseases worldwide. NAFLD is a term that involves a variety of conditions such as fatty liver, steatohepatitis, or fibrosis. Gut microbiota and its products have been extensively studied because of a close relation between NAFLD and microbiota in pathogenesis. In the progression of NAFLD, various microbiota-related molecular and cellular mechanisms, including dysbiosis, leaky bowel, endotoxin, bile acids enterohepatic circulation, metabolites, or alcohol-producing microbiota, are involved. Currently, diagnosis and treatment techniques using these mechanisms are being developed. In this review, we will introduce the microbiota-related mechanisms in the progression of NAFLD and future directions will be discussed.
Catalpol Protects ARPE-19 Cells against Oxidative Stress via Activation of the Keap1/Nrf2/ARE Pathway
Authors: You Longtai , Peng Hulinyue , Liu Jing , Cai Mengru , Wu Huimin , Zhang Zhiqin , Bai Jie , Yao Yu , Dong Xiaoxv , Yin Xingbin , Ni Jian
Published: October 2021

Oxidative damage to retinal pigment epithelial (RPE) has been identified as one of the major regulatory factors in the pathogenesis of age-related macular degeneration (AMD). Catalpol is an iridoid glucoside compound that has been found to possess potential antioxidant activity. In the present study, we aimed to investigate the protective effect of catalpol on RPE cells under oxidative stress and to elucidate the potential molecular mechanism involved. We found that catalpol significantly attenuated hydrogen peroxide (H2O2)-induced cytotoxicity, G0/G1 phase cell cycle arrest, and apoptosis in RPE cells. The overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA) stimulated by oxidative stress and the corresponding reductions in antioxidant glutathione (GSH) and superoxide dismutase (SOD) levels were largely reversed by catalpol pretreatment. Moreover, catalpol pretreatment markedly activated the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its downstream antioxidant enzymes, catalase (CAT), heme oxygenase-1 (HO-1), and NADPH dehydrogenase (NQO1). It also increased the expression levels of cyclin E, Bcl-2, cyclin A, and cyclin-dependent kinase 2 (CDK2) and decreased the expression levels of Bax, Fas, cleaved PARP, p-p53, and p21 cleaved caspase-3, 8, and 9. The oxidative stress-induced formation of the Keap1/Nrf2 complex in the cytoplasm was significantly blocked by catalpol pretreatment. These results indicate that catalpol protected RPE cells from oxidative stress through a mechanism involving the activation of the Keap1/Nrf2/ARE pathways and the inactivation of oxidative stress-mediated pathways of apoptosis.
PI3Kδ Sustains Keratinocyte Hyperproliferation and Epithelial Inflammation: Implications for a Topically Druggable Target in Psoriasis
Authors: Mercurio Laura , Morelli Martina , Scarponi Claudia , Scaglione Giovanni Luca , Pallotta Sabatino , Albanesi Cristina , Madonna Stefania
Published: October 2021

The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is aberrantly activated in psoriatic lesions and contributes to disease pathogenesis. Among PI3Ks enzymes, PI3Kα, β, and δ isoforms are known to bind the p85 regulatory subunit and mediate activation of AKT and other downstream effectors. In this study, we deepened our understanding of the expression and function of PI3Kδ in skin lesions of patients affected by psoriasis. For the first time, we found that PI3Kδ is overexpressed in psoriatic plaques, and its expression is not only confined to infiltrating immune cells but also accumulates in proliferating keratinocytes of the epidermal basal layer. We investigated the function of PI3Kδ in psoriatic skin by evaluating the impact of seletalisib, a newly developed selective PI3Kδ inhibitor, in both in vitro and in vivo experimental models of psoriasis. Of note, we found that PI3Kδ sustains keratinocyte hyperproliferation and impaired terminal differentiation induced by IL-22, as well as induces epithelial inflammation and resistance to apoptosis mediated by TNF-α in human keratinocytes. Mechanistically, PI3Kδ promotes PDK1 phosphorylation and signals through AKT-dependent or -independent pathways. It is worth mentioning that PI3Kδ inhibition by seletalisib attenuates the severity of psoriasiform phenotype induced in the Imiquimod-induced mouse model of psoriasis by restoring the physiological proliferation and differentiation programs in epidermal keratinocytes and contrasting the cutaneous inflammatory responses. Therefore, we suggest PI3Kδ as a potential topically druggable target in psoriasis and skin diseases characterized by epidermal hyperproliferation and skin inflammation.
BMP-7 Attenuates Inflammation-Induced Pyroptosis and Improves Cardiac Repair in Diabetic Cardiomyopathy
Authors: Elmadbouh Ibrahim , Singla Dinender K.
Published: October 2021

In the present study, we investigated a novel signaling target in diabetic cardiomyopathy where inflammation induces caspase-1-dependent cell death, pyroptosis, involving Nek7-GBP5 activators to activate the NLRP3 inflammasome, destabilizes cardiac structure and neovascularization. Furthermore, we explored the therapeutic ability of bone morphogenetic protein-7 (BMP-7) to attenuate these adverse effects. C57BL/6J mice (n = 16 mice/group) were divided into: control (200 mg/kg, 0.9% saline intraperitoneal injection, i.p.); Streptozotocin (STZ) and STZ-BMP-7 groups (STZ, 200 mg/kg, i.p. injection). After 6 weeks, heart function was examined with echocardiography, and mice were sacrificed. Immunostaining, Western blotting, H&E, and Masson’s trichrome staining was performed on heart tissues. STZ-induced diabetic cardiomyopathy significantly increased inflammasome formation (TLR4, NLRP3, Nek7, and GBP5), pyroptosis markers (caspase-1, IL-1β, and IL-18), inflammatory cytokines (IL-6 and TNF-α), MMP9, and infiltration of monocytes (CD14), macrophage (iNOS), and dendritic cells (CD11b and CD11c) (p < 0.05). Moreover, a significant endothelial progenitor cells (EPCs) dysfunction (c-Kit/FLk-1, CD31), adverse cardiac remodeling, and reduction in left ventricular (LV) heart function were observed in STZ versus control (p < 0.05). Treatment with BMP-7 significantly reduced inflammasome formation, pyroptosis, and inflammatory cytokines and infiltrated inflammatory cells. In addition, BMP-7 treatment enhanced EPC markers and neovascularization and subsequently improved cardiac remodeling in a diabetic heart. Moreover, a significant improvement in LV heart function was achieved after BMP-7 administration relative to diabetic mice (p < 0.05). In conclusion, BMP-7 attenuated inflammation-induced pyroptosis, adverse cardiac remodeling, and improved heart function via the TLR4-NLRP3 inflammasome complex activated by novel signaling Nek7/GBP5. Our BMP-7 pre-clinical studies of mice could have significant potential as a future therapy for diabetic patients.
Haskap Berry Phenolic Subclasses Differentially Impact Cellular Stress Sensing in Primary and Immortalized Dermal Fibroblasts
Authors: Zehfus Lily R. , Gillespie Zoe E. , Almendáriz-Palacios Carla , Low Nicholas H. , Eskiw Christopher H.
Published: October 2021

It is generally accepted that dietary phenolics from fruits are of significant importance to human health. Unfortunately, there is minimal published data on how differences in phenolic structure(s) impact biological pathways at cellular and molecular levels. We observed that haskap berry extracts isolated with ethanol:formic acid:water or phenolic subclass fractions separated using different concentrations of ethanol (40% and 100%) impacted cell growth in a positive manner. All fractions and extracts significantly increased population doubling times. All extracts and fractions reduced intracellular free radicals; however, there were differences in these effects, indicating different abilities to scavenge free radicals. The extracts and fractions also exhibited differing impacts on transcripts encoding the antioxidant enzymes (CAT, SOD1, GPX1, GSS and HMOX1) and the phosphorylation state of nuclear factor-κB (NF-κB). We further observed that extracts and fractions containing different phenolic structures had divergent impacts on the mammalian target of rapamycin (mTOR) and sirtuin 1 (SIRT1). siRNA-mediated knockdown of SIRT1 transcripts demonstrated that this enzyme is key to eliciting haskap phenolic(s) impact on cells. We postulate that phenolic synergism is of significant importance when evaluating their dietary impact.
Oxytocin Is a Positive Allosteric Modulator of κ-Opioid Receptors but Not δ-Opioid Receptors in the G Protein Signaling Pathway
Authors: Miyano Kanako , Yoshida Yuki , Hirayama Shigeto , Takahashi Hideki , Ono Haruka , Meguro Yoshiyuki , Manabe Sei , Komatsu Akane , Nonaka Miki , Mizuguchi Takaaki , Fujii Hideaki , Higami Yoshikazu , Narita Minoru , Uezono Yasuhito
Published: October 2021

Oxytocin (OT) influences various physiological functions such as uterine contractions, maternal/social behavior, and analgesia. Opioid signaling pathways are involved in one of the analgesic mechanisms of OT. We previously showed that OT acts as a positive allosteric modulator (PAM) and enhances μ-opioid receptor (MOR) activity. In this study, which focused on other opioid receptor (OR) subtypes, we investigated whether OT influences opioid signaling pathways as a PAM for δ-OR (DOR) or κ-OR (KOR) using human embryonic kidney-293 cells expressing human DOR or KOR, respectively. The CellKeyTM results showed that OT enhanced impedance induced by endogenous/exogenous KOR agonists on KOR-expressing cells. OT did not affect DOR activity induced by endogenous/exogenous DOR agonists. OT potentiated the KOR agonist-induced Gi/o protein-mediated decrease in intracellular cAMP, but did not affect the increase in KOR internalization caused by the KOR agonists dynorphin A and (-)-U-50488 hydrochloride (U50488). OT did not bind to KOR orthosteric binding sites and did not affect the binding affinities of dynorphin A and U50488 for KOR. These results suggest that OT is a PAM of KOR and MOR and enhances G protein signaling without affecting β-arrestin signaling. Thus, OT has potential as a specific signaling-biased PAM of KOR.
The Study of the Influence of Matrix, Size, Rotation Angle, and Magnetic Field on the Isothermal Entropy, and the Néel Phase Transition Temperature of Fe2O3 Nanocomposite Thin Films by the Monte-Carlo Simulation Method
Authors: Nguyen Trong Dung , Cao Long Van , Ţălu Ştefan
Published: October 2021

In this paper, the study of the influence of the matrix structure (mxm) of thin-film, rotation angle (α), magnetic field (B), and size (D) of Fe2O3 nanoparticle on the magnetic characteristic quantities such as the magnetization oriented z-direction (MzE), z-axis magnetization (Mz), total magnetization (Mtot), and total entropy (Stot) of Fe2O3 nanocomposites by Monte-Carlo (MC) simulation method are studied. The applied MC Metropolis code achieves stability very quickly, so that after 30 Monte Carlo steps (MCs), the change of obtained results is negligible, but for certainty, 84 MCs have been performed. The obtained results show that when the mxm and α increase, the magnetic phase transition appears with a very small increase in temperature Néel (TNtot). When B and D increase, TNtot increases very strongly. The results also show that in Fe2O3 thin films, TNtot is always smaller than with Fe2O3 nano and Fe2O3 bulk. When the nanoparticle size is increased to nearly 12 nm, then TNtot = T = 300 K, and between TNtot and D, there is a linear relationship: TNtot = −440.6 + 83D. This is a very useful result that can be applied in magnetic devices and in biomedical applications.
Preparation of NaA Zeolite from High Iron and Quartz Contents Coal Gangue by Acid Leaching—Alkali Melting Activation and Hydrothermal Synthesis
Authors: Kong Deshun , Jiang Rongli
Published: October 2021

In this study, NaA zeolite was successfully synthesized from coal gangue with high contents of iron and quartz as the main raw material. The results show that most iron ions can be removed from coal gangue after calcination at 700 °C for 2 h, leaching in hydrochloric acid with a mass fraction of 20% for 7 h and a liquid-solid ratio of 3.5:1. When m (acid leached residue of calcined gangue):m (Na2CO3) = 1.1 and melting at 750 °C for 2 h, the quartz and other aluminosilicates turn into nepheline, which dissolve in water. Finally, the optimum conditions of synthesis NaA zeolite are as follows: n(SiO2)/n(Al2O3) = 2.0, n(Na2O)/n(SiO2) = 2.1, n(H2O)/n(Na2O) = 55, aging at 60 °C for 2 h, and crystallization at 94 °C for 4 h. This shows that the high iron and quartz contents coal gangue can be used for the synthesis of NaA zeolite.
Spinal Manifestation of Malignant Primary (PLB) and Secondary Bone Lymphoma (SLB)
Authors: Barz Melanie , Aftahy Kaywan , Janssen Insa , Ryang Yu-Mi , Prokop Georg , Combs Stephanie E. , Jost Philipp J. , Meyer Bernhard , Gempt Jens
Published: October 2021

Manifestation of malignant lymphoma in the spine is rare; there have only been a few cases reported in the literature. Due to its rarity, there is no gold standard for the management of patients suffering from spinal lymphoma manifestations. Methods: We retrospectively reviewed the data for 37 patients (14 female, 23 male) with malignant lymphoma in the spine receiving intervention in our center from March 2006 until June 2020. Neurological impairment, pain, diagnostics, and/or surgical instability were the criteria for surgery in this patient cohort. Otherwise, only CT-guided biopsies were conducted. Analysis of the patient cohort was based on the Karnofsky performance status scale (KPSS), location of the lesion, spinal levels involved, spinal instability neoplastic score (SINS), surgical treatment, histopathological workup, adjuvant therapy, and overall survival. The following surgical procedures were performed: posterior stabilization and decompression in nine patients; decompression and/or tumor debulking in 18 patients; a two-staged procedure with dorsal stabilization and vertebral body replacement in four patients; decompression and biopsy in one patient; a two-stage procedure with kyphoplasty and posterior stabilization for one patient; posterior stabilization without decompression for one patient; a vertebroplasty and cement-augmented posterior stabilization for one patient; and a CT-guided biopsy alone for two patients. Twenty-one patients (56.78%) had ≥1 lesion in the thoracic spine, 10 patients (27.03%) had lesions in the lumbar spine, two patients had lesions in the cervicothoracic junction, two patients had lesions in the thoracolumbar junction, one patient had a lesion in the lumbosacral junction, and one patient had a lesion in the sacrum. The diagnoses of the histopathological workup were diffuse large B-cell lymphoma in 23 (62.16%) cases, indolent lymphoma in 11 (29.74%) cases, anaplastic T-cell lymphoma in one case (2.70%), T-cell lymphoma in one case (2.70%), and Burkitt lymphoma in one (2.70%) case. The median overall survival was 7.2 months (range 0.1–266.7 months). Pre- and postoperative KPSS scores were 70% (IQR 60–80%). Manifestation of malignant lymphomas in the spine is rare. Similar to the approach taken for spine metastases, a surgical intervention in cases of neurological impairment or manifest or potential instability is indicated, followed by chemoimmunotherapy and radiotherapy.
Treatment Regret, Mental and Physical Health Indicators of Psychosocial Well-Being among Prostate Cancer Survivors
Authors: Bradley Cassidy , Ilie Gabriela , MacDonald Cody , Massoeurs Lia , Vo Jasmine Dang Cam-Tu , Rutledge Robert
Published: October 2021

Prostate cancer (PCa) patients and survivors are at high risk of mental health illness. Here, we examined the contribution of treatment regret, mental and physical health indicators to the social/family, emotional, functional and spiritual well-being of PCa survivors. The study assessed 367 men with a history of PCa residing in the Maritimes Canada who were surveyed between 2017 and 2021. The outcomes were social/family, emotional, functional and spiritual well-being (FACT-P,FACIT-Sp). Predictor variables included urinary, bowel and sexual function (UCLA-PCI), physical and mental health (SF-12), and treatment regret. Logistic regression analyses were controlled for age, income, and survivorship time. Poor social/family, emotional, functional and spiritual well-being was identified among 54.4%, 26.5%, 49.9% and 63.8% of the men in the sample. Men who reported treatment regret had 3.62, 5.58, or 4.63 higher odds of poor social/family, emotional, and functional well-being, respectively. Men with low household income had 3.77 times higher odds for poor social/well-being. Good mental health was a protective factor for poor social/family, emotional, functional, or spiritual well-being. Better physical and sexual health were protective factors for poor functional well-being. Seeking to promote PCa patients’ autonomy in treatment decisions and recognizing this process’ vulnerability in health care contexts is warranted.
The Relevance of SOCS1 Methylation and Epigenetic Therapy in Diverse Cell Populations of Hepatocellular Carcinoma
Authors: Cabral Loraine Kay D. , Reyes Peter Andrew C. , Crocè Lory S. , Tiribelli Claudio , Sukowati Caecilia H. C.
Published: October 2021

The suppressor of cytokine signaling 1 (SOCS1) is a tumor suppressor gene found to be hypermethylated in cancers. It is involved in the oncogenic transformation of cirrhotic liver tissues. Here, we investigated the clinical relevance of SOCS1 methylation and modulation upon epigenetic therapy in diverse cellular populations of hepatocellular carcinoma (HCC). HCC clinical specimens were evaluated for SOCS1 methylation and mRNA expression. The effect of 5-Azacytidine (5-AZA), a demethylation agent, was assessed in different subtypes of HCC cells. We demonstrated that the presence of SOCS1 methylation was significantly higher in HCC compared to peri-HCC and non-tumoral tissues (52% vs. 13% vs. 14%, respectively, p < 0.001). In vitro treatment with a non-toxic concentration of 5-AZA significantly reduced DNMT1 protein expression for stromal subtype lines (83%, 73%, and 79%, for HLE, HLF, and JHH6, respectively, p < 0.01) compared to cancer stem cell (CSC) lines (17% and 10%, for HepG2 and Huh7, respectively), with the strongest reduction in non-tumoral IHH cells (93%, p < 0.001). 5-AZA modulated the SOCS1 expression in different extents among the cells. It was restored in CSC HCC HepG2 and Huh7 more efficiently than sorafenib. This study indicated the relevance of SOCS1 methylation in HCC and how cellular heterogeneity influences the response to epigenetic therapy.
Fifty Shades of Scandium: Comparative Study of PET Capabilities Using Sc-43 and Sc-44 with Respect to Conventional Clinical Radionuclides
Authors: Lima Thiago V. M. , Gnesin Silvano , Strobel Klaus , Pérez Maria del Sol , Roos Justus E. , Müller Cristina , van der Meulen Nicholas P.
Published: October 2021

Scandium-44 has been proposed as a valuable radionuclide for Positron Emission Tomography (PET). Recently, scandium-43 was introduced as a more favorable option, as it does not emit high-energy γ-radiation; however, its currently employed production method results in a mixture of scandium-43 and scandium-44. The interest in new radionuclides for diagnostic nuclear medicine critically depends on the option for image-based quantification. We aimed to evaluate and compare the quantitative capabilities of scandium-43/scandium-44 in a commercial PET/CT device with respect to more conventional clinical radionuclides (fluorine-18 and gallium-68). With this purpose, we characterized and compared quantitative PET data from a mixture of scandium-43/scandium-44 (~68% scandium-43), scandium-44, fluorine-18 and gallium-68, respectively. A NEMA image-quality phantom was filled with the different radionuclides using clinical-relevant lesion-to-background activity concentration ratios; images were acquired in a Siemens Biograph Vision PET/CT. Quantitative accuracy with scandium-43/scandium-44 in the phantom’s background was within 9%, which is in agreement with fluorine-18-based PET standards. Coefficient of variance (COV) was 6.32% and signal recovery in the lesions provided RCmax (recovery coefficient) values of 0.66, 0.90, 1.03, 1.04, 1.12 and 1.11 for lesions of 10-, 13-, 17-, 22-, 28- and 37-mm diameter, respectively. These results are in agreement with EARL reference values for fluorine-18 PET. The results in this work showed that accurate quantitative scandium-43/44 PET/CT is achievable in commercial devices. This may promote the future introduction of scandium-43/44-labelled radiopharmaceuticals into clinical use.