bluuebunny/crossref_metadata_2025 huggingface dataset:
Post-Irradiation Sinus Mucosa Disease in Nasopharyngeal Carcinoma Patients Treated with Intensity-Modulated Proton Therapy
Authors: Wu Pei-Wen , Huang Chien-Chia , Lee Yun-Shien , Chou Yung-Chih , Fan Kang-Hsing , Lin Chien-Yu , Huang Bing-Shen , Yang Shih-Wei , Huang Chi-Che , Chang Po-Hung , Lee Ta-Jen , Chang Joseph
Published: January 2022

In the past decade, patients with nasopharyngeal cancer (NPC) have been deemed candidates for proton radiotherapy, due to the large and comprehensive target volumes and the necessity for the retention of the surrounding healthy tissues. In this study, we aimed to compare the incidence and severity of post-irradiation sinusitis by detecting sinus mucosa diseases (SMDs) via the magnetic resonance imaging (MRI) of patients with NPC after intensity-modulated proton therapy (IMPT) and volume-modulated arc therapy (VMAT). A total of 53 patients in the IMPT group and 54 patients in the VMAT group were enrolled in this study. There were significantly lower endoscopic scores and Lund–Mackay staging scores determined from MRI scans in the IMPT group during different follow-up periods. For the most vulnerable sinuses, the incidence and severity of SMD were the highest during the third post-radiotherapy month in both groups. These decreased steadily, and there was no significant increase in the incidence and severity of SMD during the second post-radiotherapy year in the IMPT group. Our data show that NPC patients with IMPT have a significantly lower incidence and decreased severity of SMD than those with VMAT. A better and faster recovery of sinonasal function after radiotherapy in the IMPT group was also observed.
Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy
Authors: Arvanitakis Konstantinos , Koletsa Triantafyllia , Mitroulis Ioannis , Germanidis Georgios
Published: January 2022

Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with a multitude of epigenetic and extrinsic risk factors. Cancer induces myelopoiesis in the bone marrow, as well as the mobilization of hematopoietic stem and progenitor cells, which reside in the spleen. Monocytes produced in the bone marrow and the spleen further infiltrate tumors, where they differentiate into tumor-associated macrophages (TAMs). The relationship between chronic inflammation and hepatocarcinogenesis has been thoroughly investigated over the past decade; however, several aspects of the role of TAMs in HCC development are yet to be determined. In response to certain stimuli and signaling, monocytes differentiate into macrophages with antitumor properties, which are classified as M1-like. On the other hand, under different stimuli and signaling, the polarization of macrophages shifts towards an M2-like phenotype with a tumor promoting capacity. M2-like macrophages drive tumor growth both directly and indirectly, via the suppression of cytotoxic cell populations, including CD8+ T cells and NK cells. The tumor microenvironment affects the response to immunotherapies. Therefore, an enhanced understanding of its immunobiology is essential for the development of next-generation immunotherapies. The utilization of various monocyte-centered anticancer treatment modalities has been under clinical investigation, selectively targeting and modulating the processes of monocyte recruitment, activation and migration. This review summarizes the current evidence on the role of TAMs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting monocytes.
Lipid Metabolism in Cancer: The Role of Acylglycerolphosphate Acyltransferases (AGPATs)
Authors: Karagiota Angeliki , Chachami Georgia , Paraskeva Efrosyni
Published: January 2022

Altered lipid metabolism is an emerging hallmark of aggressive tumors, as rapidly proliferating cancer cells reprogram fatty acid (FA) uptake, synthesis, storage, and usage to meet their increased energy demands. Central to these adaptive changes, is the conversion of excess FA to neutral triacylglycerides (TAG) and their storage in lipid droplets (LDs). Acylglycerolphosphate acyltransferases (AGPATs), also known as lysophosphatidic acid acyltransferases (LPAATs), are a family of five enzymes that catalyze the conversion of lysophosphatidic acid (LPA) to phosphatidic acid (PA), the second step of the TAG biosynthesis pathway. PA, apart from its role as an intermediate in TAG synthesis, is also a precursor of glycerophospholipids and a cell signaling molecule. Although the different AGPAT isoforms catalyze the same reaction, they appear to have unique non-overlapping roles possibly determined by their distinct tissue expression and substrate specificity. This is best exemplified by the role of AGPAT2 in the development of type 1 congenital generalized lipodystrophy (CGL) and is also manifested by recent studies highlighting the involvement of AGPATs in the physiology and pathology of various tissues and organs. Importantly, AGPAT isoform expression has been shown to enhance proliferation and chemoresistance of cancer cells and correlates with increased risk of tumor development or aggressive phenotypes of several types of tumors.
Circulating Cell-Free DNA-Based Comprehensive Molecular Analysis of Biliary Tract Cancers Using Next-Generation Sequencing
Authors: Csoma Szilvia Lilla , Bedekovics Judit , Veres Gergő , Árokszállási Anita , András Csilla , Méhes Gábor , Mokánszki Attila
Published: January 2022

Biliary tract cancer (BTC) is a rare malignancy with a long disease course and an overall poor prognosis. Despite multiple chemotherapy agents, there is no defined second-line treatment opportunity for advanced BTCs. In the era of precision oncology, NGS plays an important role in identifying mutations that may predict the molecular pathomechanism and manage the BTC therapy. The peripheral blood liquid biopsy (LB) of cancer patients represents variable amounts of cell-free DNA (cfDNA) released from tumor foci of any anatomical location. Our study aimed to identify somatic mutations and tumor variant burden (TVB) in cell-free and matched tumor DNA. We found a positive correlation between the estimated tumor volume and cfDNA yield (r = 0.9326, p < 0.0001). Comparing tissue and LB results, similar TVB was observed. SNVs were proven in 84% of the cases, while in two cases, only the LB sample was informative for molecular analysis. The most important aberrations in BTCs, such as FGFR2, IDH1, IDH2, KRAS, and TP53, could be detected in matched LB samples. Our prospective study demonstrates a minimally invasive testing approach to identify molecular genetic alterations in cholangiocarcinoma and gallbladder cancers. Clinical applications of cfDNA reflect by capturing the outstanding spatial tumor heterogeneity and guarantee novel aspects for the precision oncology treatment.
BRCA 1/2 Germline Mutation Predicts the Treatment Response of FOLFIRINOX with Pancreatic Ductal Adenocarcinoma in Korean Patients
Authors: Park Ji Hoon , Jo Jung Hyun , Jang Sung Ill , Chung Moon Jae , Park Jeong Youp , Bang Seungmin , Park Seung Woo , Song Si Young , Lee Hee Seung , Cho Jae Hee
Published: January 2022

We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 and 2020, were pathologically confirmed to have PDAC, and had undergone targeted next-generation sequencing-based germline genetic testing. Sixty-six patients were included in the study (24 men; median age 57.5 years). In the germline test, BRCA 1/2 pathogenic mutations were found in nine patients (9/66, 13%, BRCA 1, n = 3; BRCA 2, n = 5; and BRCA 1/2, n = 1). There was no significant difference in the baseline characteristics according to BRCA mutation positivity. Among patients who underwent FOLFIRINOX chemotherapy, patients with a BRCA 1/2 mutation showed a higher overall response rate than those without a BRCA 1/2 mutation (71.4% vs. 13.9%, p = 0.004). Patients with a germline BRCA 1/2 mutation showed longer progression-free survival than those without a BRCA 1/2 mutation, without a significant time difference (18 months vs. 10 months, p = 0.297). Patients with a BRCA 1/2 mutation in the germline blood test had a higher response rate to FOLFIRINOX chemotherapy in PDAC. The high proportion of BRCA 1/2 germline mutations and response rate supports the need for germline testing in order to predict better treatment response.
Comprehensive Pan-Cancer Analyses of Pyroptosis-Related Genes to Predict Survival and Immunotherapeutic Outcome
Authors: Wang Qilin , Liu Qian , Qi Sihan , Zhang Junyou , Liu Xian , Li Xin , Li Chunyan
Published: January 2022

Pyroptosis is a newly characterized type of programmed cell death. However, its function in cancer progression and its response to treatments remain controversial. Here, we extensively and systematically compiled genes associated with pyroptosis, integrated multiomics data and clinical data across 31 cancer types from The Cancer Genome Atlas, and delineated the global alterations in PRGs at the transcriptional level. The underlying transcriptional regulations by copy number variation, miRNAs, and enhancers were elucidated by integrating data from the Genotype-Tissue Expression and International Cancer Genome Consortium. A prognostic risk model, based on the expression of PRGs across 31 cancer types, was constructed. To investigate the role of pyroptosis in immunotherapy, we found five PRGs associated with effectiveness by exploring the RNA-Seq data of patients with immunotherapy, and further identified two small-molecule compounds that are potentially beneficial for immunotherapy. For the first time, from a pyroptosis standpoint, this study establishes a novel strategy to predict cancer patient survival and immunotherapeutic outcomes.
Prognostic Factors for Localized Clear Cell Renal Cell Carcinoma and Their Application in Adjuvant Therapy
Authors: Mattila Kalle E. , Vainio Paula , Jaakkola Panu M.
Published: January 2022

Approximately 20% of patients with renal cell carcinoma (RCC) present with primarily metastatic disease and over 30% of patients with localized RCC will develop distant metastases later, after complete resection of the primary tumor. Accurate postoperative prognostic models are essential for designing personalized surveillance programs, as well as for designing adjuvant therapy and trials. Several clinical and histopathological prognostic factors have been identified and adopted into prognostic algorithms to assess the individual risk for disease recurrence after radical or partial nephrectomy. However, the prediction accuracy of current prognostic models has been studied in retrospective patient cohorts and the optimal set of prognostic features remains unclear. In addition to traditional histopathological prognostic factors, novel biomarkers, such as gene expression profiles and circulating tumor DNA, are extensively studied to supplement existing prognostic algorithms to improve their prediction accuracy. Here, we aim to give an overview of existing prognostic features and prediction models for localized postoperative clear cell RCC and discuss their role in the adjuvant therapy trials. The results of ongoing placebo-controlled adjuvant therapy trials may elucidate prognostic factors and biomarkers that help to define patients at high risk for disease recurrence.
Anticancer Activities of 9-chloro-6-(piperazin-1-yl)-11H-indeno[1,2-c] quinolin-11-one (SJ10) in Glioblastoma Multiforme (GBM) Chemoradioresistant Cell Cycle-Related Oncogenic Signatures
Authors: Mokgautsi Ntlotlang , Kuo Yu-Cheng , Tang Sung-Ling , Liu Feng-Cheng , Chen Shiang-Jiun , Wu Alexander T. H. , Huang Hsu-Shan
Published: January 2022

Current anticancer treatments are inefficient against glioblastoma multiforme (GBM), which remains one of the most aggressive and lethal cancers. Evidence has shown the presence of glioblastoma stem cells (GSCs), which are chemoradioresistant and associated with high invasive capabilities in normal brain tissues. Moreover, accumulating studies have indicated that radiotherapy contributes to abnormalities in cell cycle checkpoints, including the G1/S and S phases, which may potentially lead to resistance to radiation. Through computational simulations using bioinformatics, we identified several GBM oncogenes that are involved in regulating the cell cycle. Cyclin B1 (CCNB1) is one of the cell cycle-related genes that was found to be upregulated in GBM. Overexpression of CCNB1 was demonstrated to be associated with higher grades, proliferation, and metastasis of GBM. Additionally, increased expression levels of CCNB1 were reported to regulate activation of mitogen-activated protein kinase 7 (MAPK7) in the G2/M phase, which consequently modulates mitosis; additionally, in clinical settings, MAPK7 was demonstrated to promote resistance to temozolomide (TMZ) and poor patient survival. Therefore, MAPK7 is a potential novel drug target due to its dysregulation and association with TMZ resistance in GBM. Herein, we identified MAPK7/extracellular regulated kinase 5 (ERK5) genes as being overexpressed in GBM tumors compared to normal tissues. Moreover, our analysis revealed increased levels of the cell division control protein homolog (CDC42), a protein which is also involved in regulating the cell cycle through the G1 phase in GBM tissues. This therefore suggests crosstalk among CCNB1/CDC42/MAPK7/cluster of differentiation 44 (CD44) oncogenic signatures in GBM through the cell cycle. We further evaluated a newly synthesized small molecule, SJ10, as a potential target agent of the CCNB1/CDC42/MAPK7/CD44 genes through target prediction tools and found that SJ10 was indeed a target compound for the above-mentioned genes; in addition, it displayed inhibitory activities against these oncogenes as observed from molecular docking analysis.
Raw Biogas as Feedstock for the OCM Process
Authors: Michorczyk Barbara , Sikora Jakub , Kordon-Łapczyńska Bogusława , Gaweł Dorota , Czekaj Izabela
Published: January 2022

The paper presents the research results obtained in the process of oxidative coupling of methane, in which unpurified biogas was used as the feedstock. Biogas obtained from two kinds of biomass materials, i.e., plant materials (potato and beet pulp, Corn-Cob-Mix—biogas 1) and animal waste (waste from fish filleting—biogas 2) was considered. The influence of temperature, the ratio of methane/oxygen and total flows of feedstock on the catalytic performance in oxidative coupling of methane process was investigated. Comparative tests were carried out using pure methane and a mixture of methane-carbon dioxide to simulate the composition of biogas 2. The process was carried out in the presence of an Mn-Na2WO4/SiO2 catalyst. Fresh and used catalysts were characterised by means of powder X-ray diffraction, X-ray photoelectron spectroscopy, and low-temperature nitrogen adsorption techniques. In oxidative coupling of methane, the type of raw material used as the source of methane has a small effect on methane conversion (the differences in methane conversion are below 3%), but a significant effect on the selectivity to C2. Depending on the type of raw material, the differences in selectivity to C2 reach as high as 9%. However, the Mn-Na2WO4/SiO2 catalyst operated steadily in the tested period of time at any feedstock composition. Moreover, it was found that CO2, which is the second main component of biogas in addition to methane, has an effect on catalytic performance. Comparative results of catalytic tests indicate that the CO2 effect varies with temperature. Below 1073 K, CO2 exerts a small poisoning effect on methane conversion, while above this temperature the negative effect of CO2 disappears. In the case of selectivity to C2+, the negative effect of CO2 was observed only at 1023 K. At higher temperatures, CO2 enhances selectivity to C2+. The effect of CO2 was established by correlating the catalytic results with the temperature programmed desorption of CO2 investigation. The poisoning effect of CO2 was connected with the formation of surface Na2CO3, whose concentration depends on temperature.
Metabolomics-Guided Analysis of the Biocatalytic Conversion of Sclareol to Ambradiol by Hyphozyma roseoniger
Authors: Ncube Efficient N. , Steenkamp Paul A. , van der Westhuyzen Chris W. , Steenkamp Lucia H. , Dubery Ian A.
Published: January 2022

The biocatalytic conversion of sclareol to ambradiol, a valuable component in the fragrance industry, using whole-cell biotransformation by the dimorphic yeast Hyphozyma roseoniger, was investigated using metabolomics tools. An integrated approach was used to identify and quantify the participating intermediates in this bioconversion using both nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography coupled to mass spectrometry (LC–MS). This study entailed growth stage-dependent analysis of H. roseoniger suspensions grown in batch culture over a 14-day period, beginning with a three-day induction period using 20 mg/200 mL sclareol, followed by a further 1 g/200 mL sclareol dose to enable ambradiol production. The progress of the bioconversion and the resulting dynamic changes to the metabolome were monitored using NMR analysis and semi-targeted LC–MS metabolomics. This outlined the molecular conversions occurring within the matrix and no novel intermediates participating in the sclareol to ambradiol conversion could be identified. This study presents new findings about the transformative capabilities of H. roseoniger as a whole cell biocatalyst, highlighting its potential utility in similar applications.
Closed-Form Formulation of the Thermodynamically Consistent Electrochemical Model Considering Electrochemical Co-Oxidation of CO and H2 for Simulating Solid Oxide Fuel Cells
Authors: Kravos Andraž , Katrašnik Tomaž
Published: January 2022

Achieving efficient solid oxide fuel cell operation and simultaneous prevention of degradation effects calls for the development of precise on-line monitoring and control tools based on predictive, computationally fast models. The originality of the proposed modelling approach originates from the hypothesis that the innovative derivation procedure enables the development of a thermodynamically consistent multi-species electrochemical model that considers the electrochemical co-oxidation of carbon monoxide and hydrogen in a closed-form. The latter is achieved by coupling the equations for anodic reaction rates with the equation for anodic potential. Furthermore, the newly derived model is capable of accommodating the diffusive transport of gaseous species through the gas diffusion layer, yielding a computationally efficient quasi-one-dimensional model. This resolves a persistent knowledge gap, as the proposed modelling approach enables the modelling of multi-species fuels in a closed form, resulting in very high computational efficiency, and thus enable the model’s real-time capability. Multiple validation steps against polarisation curves with different fuel mixtures confirm the capability of the newly developed model to replicate experimental data. Furthermore, the presented results confirm the capability of the model to accurately simulate outside the calibrated variation space under different operating conditions and reformate mixtures. These functionalities position the proposed model as a beyond state-of-the-art tool for model supported development and control applications.
Altered White Matter and microRNA Expression in a Murine Model Related to Williams Syndrome Suggests That miR-34b/c Affects Brain Development via Ptpru and Dcx Modulation
Authors: Grad Meitar , Nir Ariel , Levy Gilad , Trangle Sari Schokoroy , Shapira Guy , Shomron Noam , Assaf Yaniv , Barak Boaz
Published: January 2022

Williams syndrome (WS) is a multisystem neurodevelopmental disorder caused by a de novo hemizygous deletion of ~26 genes from chromosome 7q11.23, among them the general transcription factor II-I (GTF2I). By studying a novel murine model for the hypersociability phenotype associated with WS, we previously revealed surprising aberrations in myelination and cell differentiation properties in the cortices of mutant mice compared to controls. These mutant mice had selective deletion of Gtf2i in the excitatory neurons of the forebrain. Here, we applied diffusion magnetic resonance imaging and fiber tracking, which showed a reduction in the number of streamlines in limbic outputs such as the fimbria/fornix fibers and the stria terminalis, as well as the corpus callosum of these mutant mice compared to controls. Furthermore, we utilized next-generation sequencing (NGS) analysis of cortical small RNAs’ expression (RNA-Seq) levels to identify altered expression of microRNAs (miRNAs), including two from the miR-34 cluster, known to be involved in prominent processes in the developing nervous system. Luciferase reporter assay confirmed the direct binding of miR-34c-5p to the 3’UTR of PTPRU—a gene involved in neural development that was elevated in the cortices of mutant mice relative to controls. Moreover, we found an age-dependent variation in the expression levels of doublecortin (Dcx)—a verified miR-34 target. Thus, we demonstrate the substantial effect a single gene deletion can exert on miRNA regulation and brain structure, and advance our understanding and, hopefully, treatment of WS.
Overview of Polyamines as Nutrients for Human Healthy Long Life and Effect of Increased Polyamine Intake on DNA Methylation
Authors: Soda Kuniyasu
Published: January 2022

Polyamines, spermidine and spermine, are synthesized in every living cell and are therefore contained in foods, especially in those that are thought to contribute to health and longevity. They have many physiological activities similar to those of antioxidant and anti-inflammatory substances such as polyphenols. These include antioxidant and anti-inflammatory properties, cell and gene protection, and autophagy activation. We have first reported that increased polyamine intake (spermidine much more so than spermine) over a long period increased blood spermine levels and inhibited aging-associated pathologies and pro-inflammatory status in humans and mice and extended life span of mice. However, it is unlikely that the life-extending effect of polyamines is exerted by the same bioactivity as polyphenols because most studies using polyphenols and antioxidants have failed to demonstrate their life-extending effects. Recent investigations revealed that aging-associated pathologies and lifespan are closely associated with DNA methylation, a regulatory mechanism of gene expression. There is a close relationship between polyamine metabolism and DNA methylation. We have shown that the changes in polyamine metabolism affect the concentrations of substances and enzyme activities involved in DNA methylation. I consider that the increased capability of regulation of DNA methylation by spermine is a key of healthy long life of humans.
Role of Nse1 Subunit of SMC5/6 Complex as a Ubiquitin Ligase
Authors: Kolesar Peter , Stejskal Karel , Potesil David , Murray Johanne M. , Palecek Jan J.
Published: January 2022

Structural Maintenance of Chromosomes (SMC) complexes are important for many aspects of the chromosomal organization. Unlike cohesin and condensin, the SMC5/6 complex contains a variant RING domain carried by its Nse1 subunit. RING domains are characteristic for ubiquitin ligases, and human NSE1 has been shown to possess ubiquitin-ligase activity in vitro. However, other studies were unable to show such activity. Here, we confirm Nse1 ubiquitin-ligase activity using purified Schizosaccharomyces pombe proteins. We demonstrate that the Nse1 ligase activity is stimulated by Nse3 and Nse4. We show that Nse1 specifically utilizes Ubc13/Mms2 E2 enzyme and interacts directly with ubiquitin. We identify the Nse1 mutation (R188E) that specifically disrupts its E3 activity and demonstrate that the Nse1-dependent ubiquitination is particularly important under replication stress. Moreover, we determine Nse4 (lysine K181) as the first known SMC5/6-associated Nse1 substrate. Interestingly, abolition of Nse4 modification at K181 leads to suppression of DNA-damage sensitivity of other SMC5/6 mutants. Altogether, this study brings new evidence for Nse1 ubiquitin ligase activity, significantly advancing our understanding of this enigmatic SMC5/6 function.
Carnosic Acid Attenuates the Free Fatty Acid-Induced Insulin Resistance in Muscle Cells and Adipocytes
Authors: Den Hartogh Danja J. , Vlavcheski Filip , Giacca Adria , MacPherson Rebecca E. K. , Tsiani Evangelia
Published: January 2022

Elevated blood free fatty acids (FFAs), as seen in obesity, impair insulin action leading to insulin resistance and Type 2 diabetes mellitus. Several serine/threonine kinases including JNK, mTOR, and p70 S6K cause serine phosphorylation of the insulin receptor substrate (IRS) and have been implicated in insulin resistance. Activation of AMP-activated protein kinase (AMPK) increases glucose uptake, and in recent years, AMPK has been viewed as an important target to counteract insulin resistance. We reported previously that carnosic acid (CA) found in rosemary extract (RE) and RE increased glucose uptake and activated AMPK in muscle cells. In the present study, we examined the effects of CA on palmitate-induced insulin-resistant L6 myotubes and 3T3L1 adipocytes. Exposure of cells to palmitate reduced the insulin-stimulated glucose uptake, GLUT4 transporter levels on the plasma membrane, and Akt activation. Importantly, CA attenuated the deleterious effect of palmitate and restored the insulin-stimulated glucose uptake, the activation of Akt, and GLUT4 levels. Additionally, CA markedly attenuated the palmitate-induced phosphorylation/activation of JNK, mTOR, and p70S6K and activated AMPK. Our data indicate that CA has the potential to counteract the palmitate-induced muscle and fat cell insulin resistance.
Muscle and Bone Impairment in Infantile Nephropathic Cystinosis: New Concepts
Authors: Haffner Dieter , Leifheit-Nestler Maren , Alioli Candide , Bacchetta Justine
Published: January 2022

Cystinosis Metabolic Bone Disease (CMBD) has emerged during the last decade as a well-recognized, long-term complication in patients suffering from infantile nephropathic cystinosis (INC), resulting in significant morbidity and impaired quality of life in teenagers and adults with INC. Its underlying pathophysiology is complex and multifactorial, associating complementary, albeit distinct entities, in addition to ordinary mineral and bone disorders observed in other types of chronic kidney disease. Amongst these long-term consequences are renal Fanconi syndrome, hypophosphatemic rickets, malnutrition, hormonal abnormalities, muscular impairment, and intrinsic cellular bone defects in bone cells, due to CTNS mutations. Recent research data in the field have demonstrated abnormal mineral regulation, intrinsic bone defects, cysteamine toxicity, muscle wasting and, likely interleukin-1-driven inflammation in the setting of CMBD. Here we summarize these new pathophysiological deregulations and discuss the crucial interplay between bone and muscle in INC. In future, vitamin D and/or biotherapies targeting the IL1β pathway may improve muscle wasting and subsequently CMBD, but this remains to be proven.
Accelerated Growth, Differentiation, and Ploidy with Reduced Proliferation of Right Ventricular Cardiomyocytes in Children with Congenital Heart Defect Tetralogy of Fallot
Authors: Sukhacheva Tatyana V. , Serov Roman A. , Nizyaeva Natalia V. , Burov Artem A. , Pavlovich Stanislav V. , Podurovskaya Yulia L. , Samsonova Maria V. , Chernyaev Andrey L. , Shchegolev Aleksandr I. , Kim Alexei I. , Bockeria Leo A. , Sukhikh Gennady T.
Published: January 2022

The myocardium of children with tetralogy of Fallot (TF) undergoes hemodynamic overload and hypoxemia immediately after birth. Comparative analysis of changes in the ploidy and morphology of the right ventricular cardiomyocytes in children with TF in the first years of life demonstrated their significant increase compared with the control group. In children with TF, there was a predominantly diffuse distribution of Connexin43-containing gap junctions over the cardiomyocytes sarcolemma, which redistributed into the intercalated discs as cardiomyocytes differentiation increased. The number of Ki67-positive cardiomyocytes varied greatly and amounted to 7.0–1025.5/106 cardiomyocytes and also were decreased with increased myocytes differentiation. Ultrastructural signs of immaturity and proliferative activity of cardiomyocytes in children with TF were demonstrated. The proportion of interstitial tissue did not differ significantly from the control group. The myocardium of children with TF under six months of age was most sensitive to hypoxemia, it was manifested by a delay in the intercalated discs and myofibril assembly and the appearance of ultrastructural signs of dystrophic changes in the cardiomyocytes. Thus, the acceleration of ontogenetic growth and differentiation of the cardiomyocytes, but not the reactivation of their proliferation, was an adaptation of the immature myocardium of children with TF to hemodynamic overload and hypoxemia.
T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma
Authors: Fisicaro Paola , Boni Carolina
Published: January 2022

In chronic viral hepatitis and in hepatocarcinoma (HCC), antigen-specific T cells are deeply exhausted, and evidence of dysfunction has also been observed for NK cells, which can play a pathogenetic role, exerting a regulatory activity on adaptive immune responses [...]
NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease
Authors: Mainz Rebecca Elena , Albers Stefanie , Haque Madhuri , Sonntag Roland , Treichel Nicole Simone , Clavel Thomas , Latz Eicke , Schneider Kai Markus , Trautwein Christian , Otto Tobias
Published: January 2022

A considerable percentage of the population is affected by alcoholic liver disease (ALD). It is characterized by inflammatory signals from the liver and other organs, such as the intestine. The NLR family pyrin domain containing 6 (NLRP6) inflammasome complex is one of the most important inflammatory mediators. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We showed that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we discovered significant changes of intestinal microbial communities, including increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, as well as reduced Firmicutes. In this ALD model, inhibiting NLRP6 signaling had no effect on liver steatosis or damage, but had a minor impact on intestinal homeostasis via affecting intestinal epithelium function and gut microbiota. Surprisingly, Nlrp6 loss resulted in significantly decreased hepatic immune cell infiltration. As a result, our novel mouse model encompasses several aspects of human ALD, such as intestinal dysbiosis. Interfering with NLRP6 inflammasome activity reduced hepatic immune cell recruitment, indicating a disease-aggravating role of NLRP6 during ALD.
Recent Developments in Supercapacitor Electrodes: A Mini Review
Authors: Nagarajarao Sumedha Harike , Nandagudi Apurva , Viswanatha Ramarao , Basavaraja Basavanakote Mahadevappa , Santosh Mysore Sridhar , Praveen Beekanahalli Mokshanatha , Pandith Anup
Published: January 2022

The use of nonrenewable fossil fuels for energy has increased in recent decades, posing a serious threat to human life. As a result, it is critical to build environmentally friendly and low-cost reliable and renewable energy storage solutions. The supercapacitor is a future energy device because of its higher power density and outstanding cyclic stability with a quick charge and discharge process. Supercapacitors, on the other hand, have a lower energy density than regular batteries. It is well known that the electrochemical characteristic of supercapacitors is strongly dependent on electrode materials. The current review highlights advance in the TMOs for supercapacitor electrodes. In addition, the newly discovered hybrid/pseudo-supercapacitors have been discussed. Metal oxides that are employed as electrode materials are the focus of this study. The discovery of nanostructured electrode materials continues to be a major focus of supercapacitor research. To create high-performance electrode materials from a morphological standpoint, various efforts have been attempted. Lastly, we analyze the supercapacitor’s evolving trend and our perspective for the future generations of supercapacitors.
Rational Design and Synthesis of Large Stokes Shift 2,6-Sulphur-Disubstituted BODIPYs for Cell Imaging
Authors: Reese Abigail E. , Lochenie Charles , Geddis Ailsa , Machado Luana A. , de Souza Marcos C. , Marques Flávia F. C. , de Simone Carlos A. , Gouvêa Marcos M. , Pedrosa Leandro F. , da Silva Júnior Eufrânio N. , Vendrell Marc
Published: January 2022

Five new disubstituted 2,6-thioaryl-BODIPY dyes were synthesized via selective aromatic electrophilic substitution from commercially available thiophenols. The analysis of the photophysical properties via absorption and emission spectroscopy showed unusually large Stokes shifts for BODIPY fluorophores (70–100 nm), which makes them suitable probes for bioimaging. Selected compounds were evaluated for labelling primary immune cells as well as different cancer cell lines using confocal fluorescence microscopy.
Air Pollution Exposure and Risk of Spontaneous Pneumothorax in Children: A Longitudinal, Nationwide Study
Authors: Wang Jing-Cheng , Lin Cheng-Li , Chen Chieh-Ho , Lin Chien-Heng
Published: January 2022

Spontaneous pneumothorax (SP) involves the spontaneous appearance of air in the pleural space. Atmospheric pressure, temperature change, and seasonal factors may precipitate SP, but its association with air pollution remains unclear. Therefore, we conducted this nationwide, retrospective population-based study to evaluate the risk of SP in Taiwanese children exposed to air pollution. We collected data on SP incidence from the Longitudinal Health Insurance Database; the Taiwan Air Quality-Monitoring Database provided daily concentrations of nitric oxide (NO), nitrogen dioxide (NO2), and hydrocarbons in 2000–2012. SP risk was evaluated for four quartiles (Q1, Q2, Q3, Q4). The NO adjusted hazard ratios (aHRs) for Q2, Q3, and Q4 compared to Q1 were 1.11 (95% confidence interval (CI): 0.77–1.61), 1.24 (95% CI: 0.88–1.76), and 1.66 (95% CI: 1.17–2.34), respectively. The NO2 aHRs for Q2, Q3, and Q4 were 1.12 (95% CI: 0.77–1.64), 1.31 (95% CI: 0.0.90–1.90), and 1.51 (95% CI: 1.04–2.19), respectively. Hydrocarbons aHRs for Q2, Q3, and Q4 were 0.87 (95% CI: 0.64–1.18), 1.16 (95% CI: 0.90–1.49), and 1.40 (95% CI: 1.06–1.85), respectively. Increased exposure to NO, NO2, and hydrocarbons is associated with increased SP risk in Taiwanese children.
Infants of Mothers with Cocaine Use: Review of Clinical and Medico-Legal Aspects
Authors: Cestonaro Clara , Menozzi Lorenzo , Terranova Claudio
Published: January 2022

Illicit drug use is a global problem that also affects pregnant women. Substance use and alcohol abuse during pregnancy may have various harmful consequences for both mothers and foetuses. Intrauterine exposure to illicit substances can be investigated through maternal reports and toxicological tests on mothers’ and/or newborns’ samples. While the negative effects of alcohol and opioid use on pregnancy, the foetus, and/or newborn are well established, the effects of cocaine use remain controversial. We performed a review of the literature to evaluate the current state of knowledge of the effects of intrauterine cocaine exposure on newborns’ and children’s long-term development and to highlight possible implications for health professionals dealing with women who use cocaine during pregnancy. Although intrauterine cocaine exposure has been associated with reduced infant measurements, no specific amount of cocaine use exerting such effects has been determined, and no long-term effects have been confirmed. The evidence of cocaine use during pregnancy justifies a clinical and social takeover of the mother and newborn without assuming that there will certainly be long-term damage related to intrauterine cocaine exposure, but also considering other possible associated factors.
Status of Medications Prescribed for Psychiatric Disorders in Korean Pediatric and Adolescent Patients
Authors: Jang In-Woo , Chang Ji-Eun , Kim Jongyoon , Rhew Kiyon
Published: January 2022

While mental health services for children are increasing, few psychiatric drugs have been approved for such use. We analyzed claim data from 19,557 South Korean pediatric and adolescent patients (<20 years) who were diagnosed with schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, attention deficit-hyperactivity disorder (ADHD), or a tic disorder. Among these diseases, depressive episodes were the most common, followed by an anxiety disorder, ADHD, bipolar disorder, tic disorder, and schizophrenia. For each disease, prescriptions were categorized as full-label (approved indication with pediatric dosing in the package insert (PI)), partial-label (approved indication without pediatric dosing in the PI), and contraindication (contraindicated for the specific pediatric age in the PI). For schizophrenia, major depressive disorder, and anxiety disorder, more than 50% of the patients were prescribed partial-labeled medications. Additionally, more than 5% of patients with major depressive disorder were prescribed medications that were contraindicated for their age group. Our findings reveal that children with full-labeled psychiatric conditions are commonly administered drugs that are not explicitly approved for either their disease state or age, including off-label and unlicensed drugs. To use pharmaceuticals more safely, expanding drug indications using real-world data are needed.
PNU-74654 Suppresses TNFR1/IKB Alpha/p65 Signaling and Induces Cell Death in Testicular Cancer
Authors: Chen Wen-Jung , Sung Wen-Wei , Yu Chia-Ying , Luan Yu-Ze , Chang Ya-Chuan , Chen Sung-Lang , Lee Tsung-Hsien
Published: January 2022

Testicular cancer (TC) is a rare malignancy worldwide and is the most common malignancy in males aged 15–44 years. The Wnt/β-catenin signaling pathway mediates numerous essential cellular functions and has potentially important effects on tumorigenesis and cancer progression. The search for drugs to inhibit this pathway has identified a small molecule, PNU-74654, as an inhibitor of the β-catenin/TCF4 interaction. We evaluated the therapeutic role of PNU-74654 in two TC cell lines, NCCIT and NTERA2, by measuring cell viability, cell cycle transition and cell death. Potential pathways were evaluated by protein arrays and Western blots. PNU-74654 decreased cell viability and induced apoptosis of TC cells, with significant increases in the sub G1, Hoechst-stained, Annexin V-PI-positive rates. PNU-74654 treatment of both TC cell lines inhibited the TNFR1/IKB alpha/p65 pathway and the execution phase of apoptosis. Our findings demonstrate that PNU-74654 can induce apoptosis in TC cells through mechanisms involving the execution phase of apoptosis and inhibition of TNFR1/IKB alpha/p65 signaling. Therefore, small molecules such as PNU-74654 may identify potential new treatment strategies for TC.
Possibility of SARS-CoV-2 Infection in the Metastatic Microenvironment of Cancer
Authors: Hayashi Takuma , Sano Kenji , Konishi Ikuo
Published: January 2022

According to a report from the World Health Organization (WHO), the mortality and disease severity induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are significantly higher in cancer patients than those of individuals with no known condition. Common and cancer-specific risk factors might be involved in the mortality and severity rates observed in the coronavirus disease 2019 (COVID-19). Similarly, various factors might contribute to the aggravation of COVID-19 in patients with cancer. However, the factors involved in the aggravation of COVID-19 in cancer patients have not been fully investigated so far. The formation of metastases in other organs is common in cancer patients. Therefore, the present study investigated the association between lung metastatic lesion formation and SARS-CoV-2 infectivity. In the pulmonary micrometastatic niche of patients with ovarian cancer, alveolar epithelial stem-like cells were found adjacent to ovarian cancer. Moreover, angiotensin-converting enzyme 2, a host-side receptor for SARS-CoV-2, was expressed in these alveolar epithelial stem-like cells. Furthermore, the spike glycoprotein receptor-binding domain (RBD) of SARS-CoV-2 was bound to alveolar epithelial stem-like cells. Altogether, these data suggested that patients with cancer and pulmonary micrometastases are more susceptible to SARS-CoV-2. The prevention of de novo niche formation in metastatic diseases might constitute a new strategy for the clinical treatment of COVID-19 for patients with cancer.
Melanoma Detection in Dermoscopic Images Using a Cellular Automata Classifier
Authors: Luna-Benoso Benjamín , Martínez-Perales José Cruz , Cortés-Galicia Jorge , Flores-Carapia Rolando , Silva-García Víctor Manuel
Published: January 2022

Any cancer type is one of the leading death causes around the world. Skin cancer is a condition where malignant cells are formed in the tissues of the skin, such as melanoma, known as the most aggressive and deadly skin cancer type. The mortality rates of melanoma are associated with its high potential for metastasis in later stages, spreading to other body sites such as the lungs, bones, or the brain. Thus, early detection and diagnosis are closely related to survival rates. Computer Aided Design (CAD) systems carry out a pre-diagnosis of a skin lesion based on clinical criteria or global patterns associated with its structure. A CAD system is essentially composed by three modules: (i) lesion segmentation, (ii) feature extraction, and (iii) classification. In this work, a methodology is proposed for a CAD system development that detects global patterns using texture descriptors based on statistical measurements that allow melanoma detection from dermoscopic images. Image analysis was carried out using spatial domain methods, statistical measurements were used for feature extraction, and a classifier based on cellular automata (ACA) was used for classification. The proposed model was applied to dermoscopic images obtained from the PH2 database, and it was compared with other models using accuracy, sensitivity, and specificity as metrics. With the proposed model, values of 0.978, 0.944, and 0.987 of accuracy, sensitivity and specificity, respectively, were obtained. The results of the evaluated metrics show that the proposed method is more effective than other state-of-the-art methods for melanoma detection in dermoscopic images.
Asymptomatic Hypoxemia as a Characteristic Symptom of Coronavirus Disease: A Narrative Review of Its Pathophysiology
Authors: Hirota Kiichi , Mayahara Taku , Fujii Yosuke , Nishi Kenichiro
Published: January 2022

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic and caused a huge burden to healthcare systems worldwide. One of the characteristic symptoms of COVID-19 is asymptomatic hypoxemia, also called happy hypoxia, silent hypoxemia, or asymptomatic hypoxemia. Patients with asymptomatic hypoxemia often have no subjective symptoms, such as dyspnea, even though hypoxemia is judged by objective tests, such as blood gas analysis and pulse oximetry. Asymptomatic hypoxemia can lead to acute respiratory distress syndrome, and the delay in making a diagnosis and providing initial treatment can have fatal outcomes, especially during the COVID-19 pandemic. Thus far, not many studies have covered asymptomatic hypoxemia. We present a review on the human response to hypoxemia, focusing on the respiratory response to hypoxemia rather than the pathophysiology of lung injury arising from SARS-CoV-2 infection. We have also discussed whether asymptomatic hypoxemia is specific to SARS-CoV-2 infection or a common phenomenon in lung-targeted viral infections.
Aquatic Macrophyte Vegetation Promotes Taxonomic and Functional Diversity of Odonata Assemblages in Intermittent Karst Rivers in the Mediterranean
Authors: Vilenica Marina , Rebrina Fran , Matoničkin Kepčija Renata , Šegota Vedran , Rumišek Mario , Ružanović Lea , Brigić Andreja
Published: January 2022

Assemblages of adult Odonata were studied in four intermittent karst rivers encompassing macrophyte-rich (MRH) and macrophyte-poor habitats (MPH) in southern Europe, where temporary lotic habitats are the predominant freshwater type but are still understudied. With a total of 25 recorded species, the studied habitats support species-rich Odonata assemblages, as already shown for intermittent rivers in the Mediterranean. Aquatic macrophyte abundance, conductivity, and water velocity are the most significant determinants of Odonata assemblages in the studied IRES. MRH promote higher Odonata abundance and the taxonomic and functional diversity of their assemblages compared to the MPH. Odonata assemblages in MRH are characterized by higher values of body size and a higher share of species preferring lentic and temporary hydrological conditions. Moreover, their assemblages are characterized by various patterns of nymphal development and drought resilience strategies. In contrast, MPH are preferred by lotic species, with nymphal development all year round and with no specific drought-resisting strategies. Our results contribute to the knowledge of diversity and ecological requirements of dragonflies and damselflies in IRES habitats, which could provide scientific background for future conservation activities and bioassessment protocols of such habitats and their biota.
Machine-Learning-Based Proteomic Predictive Modeling with Thermally-Challenged Caribbean Reef Corals
Authors: Mayfield Anderson B.
Published: January 2022

Coral health is currently diagnosed retroactively; colonies are deemed “stressed” upon succumbing to bleaching or disease. Ideally, health inferences would instead be made on a pre-death timescale that would enable, for instance, environmental mitigation that could promote coral resilience. To this end, diverse Caribbean coral (Orbicella faveolata) genotypes of varying resilience to high temperatures along the Florida Reef Tract were exposed herein to elevated temperatures in the laboratory, and a proteomic analysis was taken with a subset of 20 samples via iTRAQ labeling followed by nano-liquid chromatography + mass spectrometry; 46 host coral and 40 Symbiodiniaceae dinoflagellate proteins passed all stringent quality control criteria, and the partial proteomes of biopsies of (1) healthy controls, (2) sub-lethally stressed samples, and (3) actively bleaching corals differed significantly from one another. The proteomic data were then used to train predictive models of coral colony bleaching susceptibility, and both generalized regression and machine-learning-based neural networks were capable of accurately forecasting the bleaching susceptibility of coral samples based on their protein signatures. Successful future testing of the predictive power of these models in situ could establish the capacity to proactively monitor coral health.