bluuebunny/crossref_metadata_2025 huggingface dataset:
Candida albicans Sfp1 Is Involved in the Cell Wall and Endoplasmic Reticulum Stress Responses Induced by Human Antimicrobial Peptide LL-37
Authors: Hsu Chun-Min , Liao Yi-Ling , Chang Che-Kang , Lan Chung-Yu
Published: October 2021

Candida albicans is a commensal fungus of humans but can cause infections, particularly in immunocompromised individuals, ranging from superficial to life-threatening systemic infections. The cell wall is the outermost layer of C. albicans that interacts with the host environment. Moreover, antimicrobial peptides (AMPs) are important components in innate immunity and play crucial roles in host defense. Our previous studies showed that the human AMP LL-37 binds to the cell wall of C. albicans, alters the cell wall integrity (CWI) and affects cell adhesion of this pathogen. In this study, we aimed to further investigate the molecular mechanisms underlying the C. albicans response to LL-37. We found that LL-37 causes cell wall stress, activates unfolded protein response (UPR) signaling related to the endoplasmic reticulum (ER), induces ER-derived reactive oxygen species and affects protein secretion. Interestingly, the deletion of the SFP1 gene encoding a transcription factor reduced C. albicans susceptibility to LL-37, which is cell wall-associated. Moreover, in the presence of LL-37, deletion of SFP1 attenuated the UPR pathway, upregulated oxidative stress responsive (OSR) genes and affected bovine serum albumin (BSA) degradation by secreted proteases. Therefore, these findings suggested that Sfp1 positively regulates cell wall integrity and ER homeostasis upon treatment with LL-37 and shed light on pathogen-host interactions.
Drosophila Rab39 Attenuates Lysosomal Degradation
Authors: Lakatos Zsolt , Benkő Péter , Juhász Gábor , Lőrincz Péter
Published: October 2021

Lysosomal degradation, the common destination of autophagy and endocytosis, is one of the most important elements of eukaryotic metabolism. The small GTPases Rab39A and B are potential new effectors of this pathway, as their malfunction is implicated in severe human diseases like cancer and neurodegeneration. In this study, the lysosomal regulatory role of the single Drosophila Rab39 ortholog was characterized, providing valuable insight into the potential cell biological mechanisms mediated by these proteins. Using a de novo CRISPR-generated rab39 mutant, we found no failure in the early steps of endocytosis and autophagy. On the contrary, we found that Rab39 mutant nephrocytes internalize and degrade endocytic cargo at a higher rate compared to control cells. In addition, Rab39 mutant fat body cells contain small yet functional autolysosomes without lysosomal fusion defect. Our data identify Drosophila Rab39 as a negative regulator of lysosomal clearance during both endocytosis and autophagy.
Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling
Authors: Kim Jieun , Lee Hyun-ju , Park Seon Kyeong , Park Jin-Hee , Jeong Ha-Ram , Lee Soojung , Lee Heeyong , Seol Eunyoung , Hoe Hyang-Sook
Published: October 2021

The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS- and Aβ-induced neuroinflammatory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 microglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proinflammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflammasome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroinflammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphology, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and morphology. Taken together, our findings indicate that donepezil significantly downregulates LPS- and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD.
Fine Particulate Matter-Induced Oxidative Stress Mediated by UVA-Visible Light Leads to Keratinocyte Damage
Authors: Mokrzyński Krystian , Krzysztyńska-Kuleta Olga , Zawrotniak Marcin , Sarna Michał , Sarna Tadeusz
Published: October 2021

The human skin is exposed to various environmental factors including solar radiation and ambient air pollutants. Although, due to its physical and biological properties, the skin efficiently protects the body against the harm of environmental factors, their excessive levels and possible synergistic action may lead to harmful effects. Among particulate matter present in ambient air pollutants, PM2.5 is of particular importance for it can penetrate both disrupted and intact skin, causing adverse effects to skin tissue. Although certain components of PM2.5 can exhibit photochemical activity, only a limited amount of data regarding the interaction of PM2.5 with light and its effect on skin tissue are available. This study focused on light-induced toxicity in cultured human keratinocytes, which was mediated by PM2.5 obtained in different seasons. Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM) were employed to determine sizes of the particles. The ability of PM2.5 to photogenerate free radicals and singlet oxygen was studied using EPR spin-trapping and time-resolved singlet oxygen phosphorescence, respectively. Solar simulator with selected filters was used as light source for cell treatment to model environmental lightning conditions. Cytotoxicity of photoexcited PM2.5 was analyzed using MTT assay, PI staining and flow cytometry, and the apoptotic pathway was further examined using Caspase-3/7 assay and RT-PCR. Iodometric assay and JC-10 assay were used to investigate damage to cell lipids and mitochondria. Light-excited PM2.5 were found to generate free radicals and singlet oxygen in season-dependent manner. HaCaT cells containing PM2.5 and irradiated with UV-Vis exhibited oxidative stress features–increased peroxidation of intracellular lipids, decrease of mitochondrial membrane potential, enhanced expression of oxidative stress related genes and apoptotic cell death. The data indicate that sunlight can significantly increase PM2.5-mediated toxicity in skin cells.
N-Acyl Dopamines Induce Apoptosis in Endometrial Stromal Cells from Patients with Endometriosis
Authors: Gamisonia Alina M. , Yushina Marina N. , Fedorova-Gogolina Irina A. , Akimov Mikhail G. , Eldarov Chupalav M. , Pavlovich Stanislav V. , Bezuglov Vladimir V. , Gretskaya Natalia M. , Sukhikh Gennady T. , Bobrov Mikhail Yu.
Published: October 2021

Endometriosis is characterized by the formation and development of endometrial tissues outside the uterus, based on an imbalance between proliferation and cell death, leading to the uncontrolled growth of ectopic foci. The potential target for the regulation of these processes is the endocannabinoid system, which was found to be involved in the migration, proliferation, and survival of tumor cells. In this paper, we investigated the effect of endocannabinoid-like compounds from the N-acyl dopamine (NADA) family on the viability of stromal cells from ectopic and eutopic endometrium of patients with ovarian endometriosis. N-arachidonoyldopamine, N-docosahexaenoyldopamine, and N-oleoyldopamine have been shown to have a five-times-more-selective cytotoxic effect on endometrioid stromal cells. To study the mechanisms of the toxic effect, inhibitory analysis, measurements of caspase-3/9 activity, reactive oxygen species, and the mitochondrial membrane potential were performed. It was found that NADA induced apoptosis via an intrinsic pathway through the CB1 receptor and downstream serine palmitoyltransferase, NO synthase activation, increased ROS production, and mitochondrial dysfunction. The higher selectivity of NADA for endometriotic stromal cells and the current lack of effective drug treatment can be considered positive factors for further research of these compounds as possible therapeutic agents against endometriosis.
Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model
Authors: Apolloni Savina , Fabbrizio Paola , Amadio Susanna , Napoli Giulia , Freschi Mattia , Sironi Francesca , Pevarello Paolo , Tarroni Paola , Liberati Chiara , Bendotti Caterina , Volonté Cinzia
Published: October 2021

Amyotrophic lateral sclerosis (ALS) is a disease with a resilient neuroinflammatory component caused by activated microglia and infiltrated immune cells. How to successfully balance neuroprotective versus neurotoxic actions through the use of anti-inflammatory agents is still under debate. There has been a boost of awareness regarding the role of extracellular ATP and purinergic receptors in modulating the physiological and pathological mechanisms in the nervous system. Particularly in ALS, it is known that the purinergic ionotropic P2X7 receptor plays a dual role in disease progression by acting at different cellular and molecular levels. In this context, we previously demonstrated that the P2X7 receptor antagonist, brilliant blue G, reduces neuroinflammation and ameliorates some of the pathological features of ALS in the SOD1-G93A mouse model. Here, we test the novel, noncommercially available, and centrally permeant Axxam proprietary P2X7 antagonist, AXX71, in SOD1-G93A mice, by assessing some behavioral and molecular parameters, among which are disease progression, survival, gliosis, and motor neuron wealth. We demonstrate that AXX71 affects the early symptomatic phase of the disease by reducing microglia-related proinflammatory markers and autophagy without affecting the anti-inflammatory markers or motor neuron survival. Our results suggest that P2X7 modulation can be further investigated as a therapeutic strategy in preclinical studies, and exploited in ALS clinical trials.
Selenium and the 15kDa Selenoprotein Impact Colorectal Tumorigenesis by Modulating Intestinal Barrier Integrity
Authors: Canter Jessica A. , Ernst Sarah E. , Peters Kristin M. , Carlson Bradley A. , Thielman Noelle R. J. , Grysczyk Lara , Udofe Precious , Yu Yunkai , Cao Liang , Davis Cindy D. , Gladyshev Vadim N. , Hatfield Dolph L. , Tsuji Petra A.
Published: October 2021

Selenoproteins play important roles in many cellular functions and biochemical pathways in mammals. Our previous study showed that the deficiency of the 15 kDa selenoprotein (Selenof) significantly reduced the formation of aberrant crypt foci (ACF) in a mouse model of azoxymethane (AOM)-induced colon carcinogenesis. The objective of this study was to examine the effects of Selenof on inflammatory tumorigenesis, and whether dietary selenium modified these effects. For 20 weeks post-weaning, Selenof-knockout (KO) mice and littermate controls were fed diets that were either deficient, adequate or high in sodium selenite. Colon tumors were induced with AOM and dextran sulfate sodium. Surprisingly, KO mice had drastically fewer ACF but developed a similar number of tumors as their littermate controls. Expression of genes important in inflammatory colorectal cancer and those relevant to epithelial barrier function was assessed, in addition to structural differences via tissue histology. Our findings point to Selenof’s potential role in intestinal barrier integrity and structural changes in glandular and mucin-producing goblet cells in the mucosa and submucosa, which may determine the type of tumor developing.
Non-Coding RNAs in Preeclampsia—Molecular Mechanisms and Diagnostic Potential
Authors: Munjas Jelena , Sopić Miron , Stefanović Aleksandra , Košir Rok , Ninić Ana , Joksić Ivana , Antonić Tamara , Spasojević-Kalimanovska Vesna , Prosenc Zmrzljak Uršula
Published: October 2021

Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality worldwide. Defects in trophoblast invasion, differentiation of extravillous trophoblasts and spiral artery remodeling are key factors in PE development. Currently there are no predictive biomarkers clinically available for PE. Recent technological advancements empowered transcriptome exploration and led to the discovery of numerous non-coding RNA species of which microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most investigated. They are implicated in the regulation of numerous cellular functions, and as such are being extensively explored as potential biomarkers for various diseases. Altered expression of numerous lncRNAs and miRNAs in placenta has been related to pathophysiological processes that occur in preeclampsia. In the following text we offer summary of the latest knowledge of the molecular mechanism by which lnRNAs and miRNAs (focusing on the chromosome 19 miRNA cluster (C19MC)) contribute to pathophysiology of PE development and their potential utility as biomarkers of PE, with special focus on sample selection and techniques for the quantification of lncRNAs and miRNAs in maternal circulation.
Butyrylcholinesterase–Protein Interactions in Human Serum
Authors: Jasiecki Jacek , Szczoczarz Anna , Cysewski Dominik , Lewandowski Krzysztof , Skowron Piotr , Waleron Krzysztof , Wasąg Bartosz
Published: October 2021

Measuring various biochemical and cellular components in the blood is a routine procedure in clinical practice. Human serum contains hundreds of diverse proteins secreted from all cells and tissues in healthy and diseased states. Moreover, some serum proteins have specific strong interactions with other blood components, but most interactions are probably weak and transient. One of the serum proteins is butyrylcholinesterase (BChE), an enzyme existing mainly as a glycosylated soluble tetramer that plays an important role in the metabolism of many drugs. Our results suggest that BChE interacts with plasma proteins and forms much larger complexes than predicted from the molecular weight of the BChE tetramer. To investigate and isolate such complexes, we developed a two-step strategy to find specific protein–protein interactions by combining native size-exclusion chromatography (SEC) with affinity chromatography with the resin that specifically binds BChE. Second, to confirm protein complexes′ specificity, we fractionated blood serum proteins by density gradient ultracentrifugation followed by co-immunoprecipitation with anti-BChE monoclonal antibodies. The proteins coisolated in complexes with BChE were identified by mass spectroscopy. These binding studies revealed that BChE interacts with a number of proteins in the human serum. Some of these interactions seem to be more stable than transient. BChE copurification with ApoA-I and the density of some fractions containing BChE corresponding to high-density lipoprotein cholesterol (HDL) during ultracentrifugation suggest its interactions with HDL. Moreover, we observed lower BChE plasma activity in individuals with severely reduced HDL levels (≤20 mg/dL). The presented two-step methodology for determination of the BChE interactions can facilitate further analysis of such complexes, especially from the brain tissue, where BChE could be involved in the pathogenesis and progression of AD.
Translation Initiation Machinery as a Tumor Selective Target for Radiosensitization
Authors: Lehman Stacey L. , Wilson Evan D. , Camphausen Kevin , Tofilon Philip J.
Published: October 2021

Towards improving the efficacy of radiotherapy, one approach is to target the molecules and processes mediating cellular radioresponse. Along these lines, translational control of gene expression has been established as a fundamental component of cellular radioresponse, which suggests that the molecules participating in this process (i.e., the translational machinery) can serve as determinants of radiosensitivity. Moreover, the proteins comprising the translational machinery are often overexpressed in tumor cells suggesting the potential for tumor specific radiosensitization. Studies to date have shown that inhibiting proteins involved in translation initiation, the rate-limiting step in translation, specifically the three members of the eIF4F cap binding complex eIF4E, eIF4G, and eIF4A as well as the cap binding regulatory kinases mTOR and Mnk1/2, results in the radiosensitization of tumor cells. Because ribosomes are required for translation initiation, inhibiting ribosome biogenesis also appears to be a strategy for radiosensitization. In general, the radiosensitization induced by targeting the translation initiation machinery involves inhibition of DNA repair, which appears to be the consequence of a reduced expression of proteins critical to radioresponse. The availability of clinically relevant inhibitors of this component of the translational machinery suggests opportunities to extend this approach to radiosensitization to patient care.
Pantoprazole Attenuates MAPK (ERK1/2, JNK, p38)–NF-κB and Apoptosis Signaling Pathways after Renal Ischemia/Reperfusion Injury in Rats
Authors: Fawzy Michael A. , Maher Sherif A. , Bakkar Sally M. , El-Rehany Mahmoud A. , Fathy Moustafa
Published: October 2021

Ischemia/reperfusion injury (IRI) in the kidney is the most common cause of acute renal dysfunction through different cell damage mechanisms. This study aimed to investigate, on molecular basics for the first time, the effect of pantoprazole on renal IRI in rats. Different biochemical parameters and oxidative stress markers were assessed. ELISA was used to estimate proinflammatory cytokines. qRT-PCR and western blot were used to investigate the gene and protein expression. Renal histopathological examination was also performed. IRI resulted in tissue damage, elevation of serum levels of creatinine, urea nitrogen, malondialdehyde, TNF-α, IL-6, IL-1β, up-regulation of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins. Furthermore, it up-regulated the expression of the Bax gene and down-regulated the expression of the Bcl-2 gene. Treatment of the injured rats with pantoprazole, either single dose or multiple doses, significantly alleviated IRI-induced biochemical and histopathological changes, attenuated the levels of proinflammatory cytokines, down-regulated the expression of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins, and the Bax gene, and up-regulated Bcl-2 gene expression. Moreover, treatment with pantoprazole multiple doses has an ameliorative effect that is greater than pantoprazole single-dose. In conclusion, pantoprazole diminished renal IRI via suppression of apoptosis, attenuation of the pro-inflammatory cytokines’ levels, and inhibition of the intracellular signaling pathway MAPK (ERK1/2, JNK, p38)–NF-κB.
Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia
Authors: Freisleben Fabian , Modemann Franziska , Muschhammer Jana , Stamm Hauke , Brauneck Franziska , Krispien Alexander , Bokemeyer Carsten , Kirschner Karl N. , Wellbrock Jasmin , Fiedler Walter
Published: October 2021

The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.
MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells
Authors: Cassandri Matteo , Pomella Silvia , Rossetti Alessandra , Petragnano Francesco , Milazzo Luisa , Vulcano Francesca , Camero Simona , Codenotti Silvia , Cicchetti Francesca , Maggio Roberto , Festuccia Claudio , Gravina Giovanni Luca , Fanzani Alessandro , Megiorni Francesca , Catanoso Marialuigia , Marchese Cinzia , Tombolini Vincenzo , Locatelli Franco , Rota Rossella , Marampon Francesco
Published: October 2021

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS.
Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review
Authors: Güvenç Canan , Neckebroeck Fien , Antoranz Asier , Garmyn Marjan , van den Oord Joost , Bosisio Francesca Maria
Published: October 2021

Loss-of-function events in tumor suppressor genes (TSGs) contribute to the development and progression of cutaneous malignant melanoma (CMM). Epigenetic alterations are the major mechanisms of TSG inactivation, in particular, silencing by promoter CpG-island hypermethylation. TSGs are valuable tools in diagnosis and prognosis and, possibly, in future targeted therapy. The aim of this narrative review is to outline bona fide TSGs affected by promoter CpG-island hypermethylation and their functional role in the progression of CMM. We conducted a systematic literature review to identify studies providing evidence of bona fide TSGs by cell line or animal experiments. We performed a broad first search and a gene-specific second search, supplemented by reference checking. We included studies describing bona fide TSGs in CMM with promoter CpG-island hypermethylation in which inactivating mechanisms were reported. We extracted data about protein role, pathway, experiments conducted to meet the bona fide criteria and hallmarks of cancer acquired by TSG inactivation. A total of 24 studies were included, describing 24 bona fide TSGs silenced by promoter CpG-island hypermethylation in CMM. Their effect on cell proliferation, apoptosis, growth, senescence, angiogenesis, migration, invasion or metastasis is also described. These data give further insight into the role of TSGs in the progression of CMM.
Growth-Promoting Effect of Rhizobacterium (Bacillus subtilis IB22) in Salt-Stressed Barley Depends on Abscisic Acid Accumulation in the Roots
Authors: Akhtyamova Zarina , Arkhipova Tatiana , Martynenko Elena , Nuzhnaya Tatyana , Kuzmina Ludmila , Kudoyarova Guzel , Veselov Dmitry
Published: October 2021

An ABA-deficient barley mutant (Az34) and its parental cultivar (Steptoe) were compared. Plants of salt-stressed Az34 (100 mmol m−3 NaCl for 10 days) grown in sand were 40% smaller than those of “Steptoe”, exhibited a lower leaf relative water content and lower ABA concentrations. Rhizosphere inoculation with IB22 increased plant growth of both genotypes. IB22 inoculation raised ABA in roots of salt-stressed plants by supplying ABA exogenously and by up-regulating ABA synthesis gene HvNCED2 and down-regulating ABA catabolic gene HvCYP707A1. Inoculation partially compensated for the inherent ABA deficiency of the mutant. Transcript abundance of HvNCED2 and related HvNCED1 in the absence of inoculation was 10 times higher in roots than in shoots of both mutant and parent, indicating that ABA was mainly synthesized in roots. Under salt stress, accumulation of ABA in the roots of bacteria-treated plants was accompanied by a decline in shoot ABA suggesting bacterial inhibition of ABA transport from roots to shoots. ABA accumulation in the roots of bacteria-treated Az34 was accompanied by increased leaf hydration, the probable outcome of increased root hydraulic conductance. Thereby, we tested the hypothesis that the ability of rhizobacterium (Bacillus subtilis IB22) to modify responses of plants to salt stress depends on abscisic acid (ABA) accumulating in roots.
Poly ADP Ribose Polymerase Inhibitor Olaparib Targeting Microhomology End Joining in Retinoblastoma Protein Defective Cancer: Analysis of the Retinoblastoma Cell-Killing Effects by Olaparib after Inducing Double-Strand Breaks
Authors: Jiang Yuning , Yam Jason C. , Chu Wai Kit
Published: October 2021

Retinoblastoma is the most common intraocular cancer in childhood. Loss of function in both copies of the RB1 gene is the causal mutation of retinoblastoma. Current treatment for retinoblastoma includes the use of chemotherapeutic agents, such as the DNA damaging agent etoposide, which is a topoisomerase II poison that mainly generates DNA double-strand breaks (DSBs) and genome instability. Unfaithful repairing of DSBs could lead to secondary cancers and serious side effects. Previously, we found that RB knocked-down mammalian cells depend on a highly mutagenic pathway, the micro-homology mediated end joining (MMEJ) pathway, to repair DSBs. Poly ADP ribose polymerase 1 (PARP1) is a major protein in promoting the MMEJ pathway. In this study, we explored the effects of olaparib, a PARP inhibitor, in killing retinoblastoma cells. Retinoblastoma cell line Y79 and primary retinoblastoma cells expressed the cone-rod homeobox protein (CRX), a photoreceptor-specific marker. No detectable RB expression was found in these cells. The co-treatment of olaparib and etoposide led to enhanced cell death in both the Y79 cells and the primary retinoblastoma cells. Our results demonstrated the killing effects in retinoblastoma cells by PARP inhibitor olaparib after inducing DNA double-strand breaks. The use of olaparib in combination with etoposide could improve the cell-killing effects. Thus, lower dosages of etoposide can be used to treat retinoblastoma, which would potentially lead to a lower level of DSBs and a relatively more stable genome.
Andean Plants Essential Oils: A Scented Alternative to Synthetic Insecticides for the Control of Blowflies
Authors: Farina Priscilla , Venturi Francesca , Ascrizzi Roberta , Flamini Guido , Chiriboga Ortega Rodrigo Daniel , Echeverría Maria Cristina , Ortega Sania , Zinnai Angela , Bedini Stefano , Conti Barbara
Published: October 2021

Blowflies are vectors of microorganisms and human pathogens, and their maggots cause myiasis in vertebrates and infest and spoil meat and fish products. Essential oils (EOs) from spices were proven to be a safer and more sustainable alternative to synthetic insecticides for the control of blowflies and are suitable for protecting food from such pests. However, some EOs are not acceptable for environmental or topical applications due to their strong, unpleasant odour. In this study, we measured the acute toxicity and the repellence of two EOs extracted from the Andean plants Aloysia citrodora Palau and Bursera graveolens (Kunth) Triana and Planch., both known for their pleasant odour, against the blue blowfly Calliphora vomitoria (L.) (Diptera: Calliphoridae). We also compared their bioactivity with that of the Allium sativum L. EO, which is very effective but bad-smelling. The A. citrodora EO was mainly rich in oxygenated monoterpenes, the most abundant of which were geranial (26.8%) and neral (21.0%). The B. graveolens EO was chiefly composed of monoterpene hydrocarbons, mostly represented by limonene (46.2%). According to the sensory description, the best odour profile was associated with the A. citrodora EO, while the olfactory expression of the EO from B. graveolens was negatively affected by a strong odour of “mouldy lemon”. The behavioural test showed that the A. citrodora EO was more repellent than that of A. sativum and, on the contrary, that the B. graveolens EO was attractive. The toxicity tests showed that the EOs of both Andean plants have a clear toxic effect on the C. vomitoria eggs and adults. In terms of ovicidal activity, there were no significant differences among the effects of the three tested EOs. On the adult flies, the toxicity of the two EOs of the Andean plants was much lower than that of A. sativum (LC50 fumigation = 1.86 μL EO L−1 air; LC50 ingestion = 8.10 μL EO mL−1 gel) both by fumigation (LC50 = 23.66 and 25.30 μL EO L−1 air for A. citrodora and B. graveolens, respectively) and ingestion (LC50 = 36.65 and 44.97 μL EO mL−1 gel for A. citrodora and B. graveolens, respectively), while, by contact, the A. citrodora EO (LD50 = 0.27 μL EO insect−1) was more toxic than the A. sativum EO (LD50 = 0.46 μL EO insect−1).
Changes in Tongue Area, Pharyngeal Area, and Pharyngeal Airway Velocity after Correction of Mandibular Prognathism
Authors: Chen Chun-Ming , Yu Ting-Ying , Chou Szu-Ting , Cheng Jung-Hsuan , Chen Shih-Chieh , Pan Chin-Yun , Tseng Yu-Chuan
Published: October 2021

This study aimed to investigate the correlation between the amount of mandibular setback, and the related changes of the tongue area, pharyngeal area, and pharyngeal airflow velocity. Twenty-five patients treated for mandibular prognathism, and serial cephalograms were obtained (T1: preoperation, T2: more than one year postoperation). The postoperative area of the tongue, pharyngeal airway space, and pharyngeal airflow velocity were investigated. Statistical analysis was performed with the Student t-test and Pearson correlation. The amount of mandible setback was significant after surgery (12.8 mm; p < 0.001). The pharyngeal area was significantly reduced 115.5 mm2 (p = 0.046). There was a slight reduction of the tongue area (43.2 mm2; p = 0.305) and an increase of pharyngeal airflow velocity (0.3 m/s; p = 0.133). The Pearson correlation coefficient test showed no statistical significance among the amount of horizontal setback and vertical movement of the mandible, such as the reductions in the tongue area, the pharyngeal airway space, and the increase in pharyngeal airflow velocity. Larger amounts of mandibular setback caused a significant reduction of pharyngeal airway area, but without significant changes of the tongue area and pharyngeal airflow velocity.
Evaluation of Radiographic Contrast-Induced Nephropathy by Functional Diffusion Weighted Imaging
Authors: Thiel Thomas Andreas , Schweitzer Julian , Xia Taogetu , Bechler Eric , Valentin Birte , Steuwe Andrea , Boege Friedrich , Westenfeld Ralf , Wittsack Hans-Jörg , Ljimani Alexandra
Published: October 2021

Contrast-induced nephropathy (CIN) resembles an important complication of radiographic contrast medium (XCM) displayed by a rise in creatinine levels 48–72 h after XCM administration. The purpose of the current study was to evaluate microstructural renal changes due to CIN in high-risk patients by diffusion weighted (DWI) and diffusion tensor imaging (DTI). Fifteen patients (five CIN and ten non-CIN) scheduled for cardiological intervention were included in the study. All patients were investigated pre- and post-intervention on a clinical 3T scanner. After anatomical imaging, renal DWI was performed by a paracoronal echo-planar-imaging sequence. Renal clinical routine serum parameters and advanced urinary injury markers were determined to monitor renal function. We observed a drop in cortical and medullar apparent diffusion coefficient (ADC) and fractional anisotropy (FA) before and after XCM administration in the CIN group. In contrast, the non-CIN group differed only in medullary ADC. The decrease of ADC and FA was apparent even before serum parameters of the kidney changed. In conclusion, DWI/DTI may be a useful tool for monitoring high-risk CIN patients as part of multi-modality based clinical protocol. Further studies, including advanced analysis of the diffusion signal, may improve the identification of patients at risk for CIN.
Exploring Implementation of Personal Breast Cancer Risk Assessments
Authors: Sierra Maria A. , Wheeler Jack C. W. , Devereux Lisa , Trainer Alison H. , Keogh Louise
Published: October 2021

Personal Breast Cancer (BC) Risk Assessments (PBCRA) have potential to stratify women into clinically-actionable BC risk categories. As this could involve population-wide genomic testing, women’s attitudes to PBCRA and views on acceptable implementation platforms must be considered to ensure optimal population participation. We explored these issues with 31 women with different BC risk profiles through semi-structured focus group discussions or interviews. Inductive thematic coding of transcripts was performed. Subsequently, women listed factors that would impact on their decision to participate. Participants’ attitudes to PBCRA were positive. Identified themes included that PBCRA acceptance hinges on result actionability. Women value the ability to inform decision-making. Participants reported anxiety, stress, and genetic discrimination as potential barriers. The age at which PBCRA was offered, ease of access, and how results are returned held importance. Most women value the opportunity for PBCRA to inform increased surveillance, while highlighting hesitance to accept reduced surveillance as they find reassurance in regular screening. Women with BRCA pathogenic variants value the potential for PBCRA to identify a lower cancer risk and potentially inform delayed prophylactic surgery. This study highlights complexities in adopting advances in BC early detection, especially for current users who value existing processes as a social good.
Association of Pulmonary Function Decline over Time with Longitudinal Change of Glycated Hemoglobin in Participants without Diabetes Mellitus
Authors: Lee Wen-Hsien , Wu Da-Wei , Chen Ying-Chih , Liu Yi-Hsueh , Liao Wei-Sheng , Chen Szu-Chia , Hung Chih-Hsing , Kuo Chao-Hung , Su Ho-Ming
Published: October 2021

Pulmonary damage and function impairment were frequently noted in patients with diabetes mellitus (DM). However, the relationship between lung function and glycemic status in non-DM subjects was not well-known. Here, we evaluated the association of longitudinal changes of lung function parameters with longitudinal changes of glycated hemoglobin (HbA1c) in non-DM participants. The study enrolled participants without prior type 2 DM, hypertension, and chronic obstructive pulmonary disease (COPD) from the Taiwan Biobank database. Laboratory profiles and pulmonary function parameters, including forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), were examined at baseline and follow-up. Finally, 7055 participants were selected in this study. During a mean 3.9-year follow-up, FVC and FEV1 were significantly decreased over time (both p < 0.001). In the multivariable analysis, the baseline (unstandardized coefficient β = −0.032, p < 0.001) and longitudinal change (unstandardized coefficient β = −0.025, p = 0.026) of FVC were negatively associated with the baseline and longitudinal change of HbA1c, respectively. Additionally, the longitudinal change of FVC was negatively associated with the risk of newly diagnosed type 2 DM (p = 0.018). During a mean 3.9-year follow-up, our present study, including participants without type 2 DM, hypertension, and COPD, demonstrated that the baseline and longitudinal change of FVC were negatively and respectively correlated with the baseline and longitudinal change of HbA1c. Furthermore, compared to those without new-onset DM, participants with new-onset DM had a more pronounced decline of FVC over time.
Engagement of Ethnic-Minority Consumers with Electronic Word of Mouth (eWOM) on Social Media: The Pivotal Role of Intercultural Factors
Authors: Levy Shalom , Gvili Yaniv , Hino Hayiel
Published: October 2021

Social network sites (SNS) facilitate eWOM communication among consumers of different cultures. Building on contact theory and the theory of planned behavior, we propose a conceptual framework that integrates intercultural factors as predictors of minority consumers’ engagement with eWOM communicated by and to individuals of the dominant culture on social media. A partial least squares (PLS) analysis on data collected from the Israeli-Arab minority shows that intercultural factors (i.e., acculturation, social interaction, and language proficiency) are antecedents of minority consumer engagement with eWOM. However, this relationship is mediated by consumer beliefs (attitudes, subjective norms, and perceived behavioral control) concerning this behavior, and moderated by the cultural distance between minority and dominant culture consumers. The findings help marketers plan marketing communications that engage audiences meaningfully and generate positive eWOM when targeting ethnic-cultural minorities. The current study contributes to our understanding of minority consumers’ engagement with eWOM communicated by and to members of the hegemonic culture. It further contributes to consumer engagement theory and acculturation research by supporting the post-assimilationist view. The proposed model is highly valuable in light of the importance of the concept of consumer engagement in marketing research.
The Role of Small Woody Landscape Features and Agroforestry Systems for National Carbon Budgeting in Germany
Authors: Golicz Karolina , Ghazaryan Gohar , Niether Wiebke , Wartenberg Ariani C. , Breuer Lutz , Gattinger Andreas , Jacobs Suzanne R. , Kleinebecker Till , Weckenbrock Philipp , Große-Stoltenberg André
Published: October 2021

The intensification of food production systems has resulted in landscape simplification, with trees and hedges disappearing from agricultural land, principally in industrialized countries. However, more recently, the potential of agroforestry systems and small woody landscape features (SWFs), e.g., hedgerows, woodlots, and scattered groups of trees, to sequester carbon was highlighted as one of the strategies to combat global climate change. Our study was aimed to assess the extent of SWFs embedded within agricultural landscapes in Germany, estimate their carbon stocks, and investigate the potential for increasing agroforestry cover to offset agricultural greenhouse gas (GHG) emissions. We analyzed open-source geospatial datasets and identified over 900,000 hectares of SWFs on agricultural land, equivalent to 4.6% of the total farmland. The carbon storage of SWFs was estimated at 111 ± 52 SD teragrams of carbon (Tg C), which was previously unaccounted for in GHG inventories and could play a role in mitigating the emissions. Furthermore, we found cropland to have the lowest SWF density and thus the highest potential to benefit from the implementation of agroforestry, which could sequester between 0.2 and 2 Tg of carbon per year. Our study highlights that country-specific data are urgently needed to refine C stock estimates, improve GHG inventories and inform the large-scale implementation of agroforestry in Germany.
Territorial Analysis of the Survival of European Aid to Rural Tourism (Leader Method in SW Spain)
Authors: Engelmo Moriche Ángela , Nieto Masot Ana , Mora Aliseda Julián
Published: October 2021

Due to the problems of the European rural environment, the European Union introduced territorial development strategies called the Leader Method (LEADER Initiatives and the now extinct PRODER Operational Programs implemented only in Spanish territory). The objective was to activate the economic development of these areas, to maintain the population and to slow down the migration and aging processes. During the last 25 years, these initiatives have been implemented in European rural areas, and more particularly in Extremadura, establishing new activities such as rural tourism, which has become the economic backbone of many families, complementing agricultural incomes. The development of rural tourism has led to the implementation of accommodation and catering services throughout Extremadura, adapting to the new tourist demands. However, after 25 years, its sustainability has been very different, with contextual variables that have conditioned its success. Therefore, it is necessary to analyze the economic sustainability of the tourism offer financed by Leader and the extinct Proder in order to identify the factors that have determined its success in a territory with very diverse characteristics. For this purpose, a methodology based on two statistical analysis techniques (principal component analysis and cluster analysis) has been designed to establish behavioral patterns through the different context variables used. The results obtained have shown that factors such as investment, location, the presence of protected resources and accessibility are determining factors for the survival of the tourism offer.
Neoadjuvant Immunotherapy in Resectable Non-Small Cell Lung Cancer. A Narrative Review
Authors: Gatteschi Lavinia , Iannopollo Mauro , Gonfiotti Alessandro
Published: October 2021

Lung cancer is one of the most common malignant tumors and it is the leading cause of cancer-related mortality worldwide. For early-stage Non-Small Cell Lung Cancer (NSCLC), surgical resection is the treatment of choice, but the 5-year survival is still unsatisfying, ranging from 60% to 36% depending on the disease stage. Multimodality treatment with adjuvant chemotherapy did not lead to clinically relevant results, improving survival rates by only 5%. Recently, immune checkpoint inhibitors (ICIs) are being studied as neoadjuvant treatment for resectable NSCLC too, after the satisfactory results obtained in stage IV disease. Several clinical trials are evaluating the safety and feasibility of neoadjuvant immunotherapy and their early findings suggest that ICIs could be better tolerated than standard neoadjuvant chemotherapy and more effective in reducing cancer local recurrence and metastasis. The aim of this review is to retrace the most relevant results of the completed and the ongoing clinical trials, in terms of efficacy and safety, but also to face the open challenges regarding ICIs in neoadjuvant setting for resectable NSCLC.
Sulfidation-Oxidation Resistance of Thermal Diffusion Multi-Layered Coatings on Steels
Authors: Dudziak Tomasz P. , Rząd Ewa , Medvedovski Eugene , Mendoza Gerardo Leal
Published: October 2021

The high-temperature sulfidation-oxidation corrosion resistance of protective coatings deposited on carbon and 316L steels was studied. The coatings obtained via the thermal diffusion process had multi-layered architectures and consisted of aluminides, iron borides, or iron boride–TiO2 layers. The protective coatings experienced a minimal rate of mass changes, insignificant scale formation, and no delamination and surface micro-cracking after 504 h of exposure in 1% (Vol.) H2S-air atmosphere at 500 °C. Furthermore, the coatings demonstrated a high degree of integrity compared to bare 316L stainless steel. Aluminized steels demonstrated the highest performance among the studied materials. The developed thermal diffusion coatings are promising candidates due to their enhanced stability in H2S–air atmosphere; they may be employed for protection of inner and outer surfaces of long tubing and complex shape components.
Biopolymer Degradation Analysis: Accelerated Life Testing Study to Characterize Polylactic Acid Durability
Authors: Arias-Nava Elias H. , Sullivan B. Patrick , Valles-Rosales Delia J.
Published: October 2021

While the degradation of Polylactic Acid (PLA) has been studied for several years, results regarding the mechanism for determining degradation are not completely understood. Through accelerated degradation testing, data can be extrapolated and modeled to test parameters such as temperature, voltage, time, and humidity. Accelerated lifetime testing is used as an alternative to experimentation under normal conditions. The methodology to create this model consisted of fabricating series of ASTM specimens using extrusion and injection molding. These specimens were tested through accelerated degradation; tensile and flexural testing were conducted at different points of time. Nonparametric inference tests for multivariate data are presented. The results indicate that the effect of the independent variable or treatment effect (time) is highly significant. This research intends to provide a better understanding of biopolymer degradation. The findings indicated that the proposed statistical models can be used as a tool for characterization of the material regarding the durability of the biopolymer as an engineering material. Having multiple models, one for each individual accelerating variable, allow deciding which parameter is critical in the characterization of the material.
Integrating Electronics to Textiles by Ultrasonic Welding for Cable-Driven Applications for Smart Textiles
Authors: Micus Sebastian , Rostami Sahar Golmohammadi , Haupt Michael , Gresser Götz T. , Meghrazi Milad Alizadeh , Eskandarian Ladan
Published: October 2021

The connection between flexible textiles and stiff electronic components has always been structurally weak and a limiting factor in the establishment of smart textiles in our everyday life. This paper focuses on the formation of reliable connections between conductive textiles and conventional litz wires using ultrasonic welding. The paper offers a promising approach to solving this problem. The electrical and mechanical performance of the samples were investigated after 15 and 30 wash-and-dry cycles in a laundry machine. Here the contact resistances and their peeling strength were measured. Furthermore, their connection properties were analysed in microsections. The resistance of the joints increased more than 300%, because the silver-coated wires suffered under the laundry cycles. Meanwhile, the mechanical strength during the peeling test decreased by only about 20% after 15 cycles and remained the same after 30 cycles. The good results obtained in this study suggest that ultrasonic welding offers a useful approach to the connection of textile electronics to conductive wires and to the manufacture of smart textiles.