Search

Background Commensal bacteria secrete metabolites that reach distant cancer cells through the circulation and influence cancer behavior. Deoxycholic acid (DCA), a hormone-like metabolite, is a secondary bile acid specifically synthesized by intestinal microbes. DCA may have both pro- and antineoplastic effects in cancers. Methods and results The pancreatic adenocarcinoma cell lines, Capan-2 and BxPC-3, were treated with 0.7 µM DCA, which corresponds to the reference concentration of DCA in human serum. DCA influenced the expression of epithelial to mesenchymal transition (EMT)-related genes, significantly decreased the expression level of the mesenchymal markers, transcription factor 7- like 2 (TCF7L2), snail family transcriptional repressor 2 (SLUG), CLAUDIN-1, and increased the expression of the epithelial genes, zona occludens 1 (ZO-1) and E-CADHERIN, as shown by real-time PCR and Western blotting. Consequently, DCA reduced the invasion capacity of pancreatic adenocarcinoma cells in Boyden chamber experiments. DCA induced the protein expression of oxidative/nitrosative stress markers. Moreover, DCA reduced aldehyde dehydrogenase 1 (ALDH1) activity in an Aldefluor assay and ALDH1 protein level, suggesting that DCA reduced stemness in pancreatic adenocarcinoma. In Seahorse experiments, DCA induced all fractions of mitochondrial respiration and glycolytic flux. The ratio of mitochondrial oxidation and glycolysis did not change after DCA treatment, suggesting that cells became hypermetabolic. Conclusion DCA induced antineoplastic effects in pancreatic adenocarcinoma cells by inhibiting EMT, reducing cancer stemness, and inducing oxidative/nitrosative stress and procarcinogenic effects such as hypermetabolic bioenergetics.

The varying efficacy of biased and balanced agonists is generally explained by the stabilization of different active receptor conformations. In this study, systematic profiling of transducer activation of AT1angiotensin receptor agonists revealed that the extent and kinetics of β-arrestin binding exhibit substantial ligand-dependent differences, which however completely disappear upon the inhibition of receptor internalization. Even weak partial agonists for the β- arrestin pathway acted as full or near full agonists, if receptor endocytosis was prevented, indicating that receptor conformation is not an exclusive determinant of β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation at endosomes was much larger than it was at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway is spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shape the effects of agonists on endosomal receptor–β-arrestin binding and thus determine the extent of bias. Among others, ligand dissociation rate and G protein activity have particularly strong impact on receptor–β-arrestin interaction, and their effects are integrated at endosomes. Our results highlight that endocytosis forms a key spatiotemporal platform for biased GPCR signaling and can aid the development of more efficacious functionally-selective compounds.One Sentence summaryAgonist-specific differences in β-arrestin recruitment are mainly determined by the ligand dissociation rate and G protein activation at the endosomes.

Relying on an interview-based research carried out in Szeklerland (Eastern Transylvania) between 2011 and 2020, the present study investigates the impact of the new rural development paradigm on the first level indicated by Van der Ploeg et al. (2000): changes in the relationship between agriculture and local society. The analysed region does not form an administrative unit, it is the eastern region of the former Austro-Hungarian monarchy. It consists of rural settlements and small towns, the population of which is mostly of Hungarian ethnicity. More than half of the households have a small amount of land and are engaged in farming as their main or supplementary activity. Following a brief overview of the regional context, our paper analyzes the essential changes that have been taking place in the relationship between agriculture and the regional society over the last one or two decades. The focus of the analysis is how changes in the relationship between agriculture and the regional society appear in the innovative agricultural entrepreneurs’ practice and interpretations.

A székelyföldi térség innovatív agrárvállalkozásai bizonyos mértékben betagolódnak abba a társadalmi és térbeli dimenzióba, amelyben létrejönnek és tevékenységük által többletet visznek a ruralitásba. Ez a folyamat az agrárvállalkozók közvetlen környezetében rendelkezésére álló belső, helyi erőforrások és különböző globális, külső hatások eredményeként alakul ki. A családi kontextushoz képest külsőnek tekinthető a külföldön szerzett tapasztalat, a térségben korábban létező innovatív gyakorlat átvétele, a képzési programokon való részvétel, a támogatási források felhasználása, a térségi szakember segítségének igénybevétele, valamint az intézményes rendszerben szerzett előzetes tudás. A tanulmányban harminchárom térségi agrárvállalkozóval készített interjú szövegeiben azonosítom és vizsgálom ezt a hat típust.

PARP enzymes are involved in metabolic regulation and impact on a plethora of cellular metabolic pathways, among them, mitochondrial oxidative metabolism. The detrimental effects of PARP1 overactivation upon oxidative stress on mitochondrial oxidative metabolism was discovered in 1998. Since then, there was an enormous blooming in the understanding of the interplay between PARPs and mitochondria. Mitochondrial activity can be assessed by a comprehensive set of methods that we aim to introduce here.

Namen prispevka je pomagati razumeti, kako se je odnosno zaupanje med ucenci in ucitelji, vgrajeno v proces poucevanja in ucenja, razvijalo med izrednim izobraževanjem na daljavo in prilagodljivim hibridnim izobraževanjem v Srbiji leta 2020. Opredeljuje tudi situacije v odnosih med ucenci in ucitelji, ki imajo potencial za obnovo in krepitev zaupanja. Da bi odnos med ucencem in uciteljem temeljil na zaupanju ter tako pripomogel k ucenju in dobremu pocutju ucencev, je treba doseci soglasje o pricakovanjih glede vlog. Ker je kriza covida-19 prekinila solanje in izobraževanje, so se udeleženci spoprijeli z negotovostjo in dvoumnostjo pri uveljavljanju vlog, poruseni pa so bili tudi temelji odnosnega zaupanja. Da bi razumeli kontekst, v katerem je bilo zaupanje postavljeno pod vprasaj, nacine, na katere je bilo poruseno, in priložnosti za njegovo ponovno vzpostavitev, smo se pri zbiranju podatkov oprli na vecvrstni pristop dinamicnega pripovedovanja zgodb, pri obdelavi podatkov pa na analizo vrednot. Skupaj 136 ucencev in 117 uciteljev iz 22 sol je napisalo 581 pripovedi treh vrst: zgodbe, pisma in prosnje. Analiza je dala 22 kod, ki so omogocile nadaljnje razumevanje, kako so spremembe strukturnih in institucionalnih pogojev vplivale na medsebojna pricakovanja ucencev in uciteljev ter kako se je neskladnost teh pricakovanj odrazila v obcutkih nemoci pri ucencih in uciteljih, neudeležbi pri ucenju pri ucencih ter v veliki delovni obremenitvi in slabi ucinkovitosti pri uciteljih. Poleg tega pripovedi opisujejo pozitivne rezultate, ko so bila ta pricakovanja izpolnjena, in priložnosti za krepitev zaupanja, ce se na stalisca ucencev in uciteljev opozori ter se o njih pogaja na lokalni ravni. Na koncu so podana priporocila za ponovno vzpostavitev zaupanja.Alternate abstract:This paper aims to help understand how relational trust between students and teachers embedded in the teaching-learning process unfolded during the emergency distance and flexible hybrid education in Serbia in 2020. It also identifies niches in student-teacher relationships that hold potential for repairing and building trust. For the student-teacher relationship to be trust-based and thus conducive to students learning and wellbeing, a consensus about role expectations must be achieved. As the Covid-19 crisis interrupted schooling and education, participants faced uncertainties and ambiguities in role enactment, and the cornerstones of relational trust were disrupted. In an effort to understand 1) the context in which trust was challenged, 2) the ways in which trust was disrupted, and 3) the opportunities for its restoration, we relied on a multi-genre dynamic storytelling approach to data collection and values analysis for data processing. A total of 136 students and 117 teachers from 22 schools wrote 581 narratives in three genres: stories, letters and requests. The analysis yielded 22 codes that allowed further understanding of how changes in structural and institutional conditions affected both students and teachers expectations of each other, and how incongruence of these expectations fed into feelings of helplessness for both students and teachers, disengagement from learning for students, and heavy workload and poor performance for teachers. In addition, the narratives account for positive outcomes when these expectations were met, and for opportunities for trust-building if students and teachers perspectives are brought to each others attention and negotiated locally. Finally, recommendations for restoring trust are given.

Social inclusion is a goal of 21st-century education and social welfare, yet research with violently displaced youth leaves gaps in its meaning. Social inclusion, a societal aim, lacks the perspectives of youth at its center. Given the pressures and power relations involved in learning how young people think and feel about social injustices and the support they need, developmental researchers must find innovative ways to study youth experiences and intentions in relation to environments, especially environments that threaten young lives. Emerging research highlights how displaced youth, peers along their journeys, and adults guiding supportive interventions make audible the meaning of social inclusion. Policy paradigms would benefit from research on sense-making in interventions rather than from emphasizing behavioral assessments and assimilation to local norms, as implied by social inclusion.

The aim of this paper is to thoroughly examine how students in Serbia experienced their education through distance learning during the 2020 Spring school closures due to the pandemic. Schoolchildren's multigenre narratives about learning during school closure were elicited by online surveys; qualitative thematic and values analyses were conducted; and data was further analysed by cluster analysis, ANOVA, and t-tests. A total of 45 lower and upper secondary school students produced 106 narratives providing 429 thought units for analysis. Altogether, 6 themes and 26 value codes were identified. They demonstrate the wide range, complexity, and nuanced positioning of students' experiences towards the new situation, their role in it, and the role of others i.e. teachers and the technology itself. The paper draws implications on the policy and educational-psychological and methodological level.

Comprehensive analysis of post-translation modifications (PTMs) is an important mission of proteomics. However, the consideration of PTMs increases the search space and may therefore impair the efficiency of protein identification. Using thousands of proteomic searches, we investigated the practical aspects of considering multiple PTMs in Byonic searches for the maximization of protein and peptide hits. The inclusion of all PTMs, which occur with at least 2% frequency in the sample, has an advantageous effect on protein and peptide identification. A linear relationship was established between the number of considered PTMs and the number of reliably identified peptides and proteins. Even though they handle multiple modifications less efficiently, the results of MASCOT (using the Percolator function) and Andromeda (the search engine included in MaxQuant) became comparable to those of Byonic, in the case of a few PTMs.

A hybrid powder of Ti6Al4V, which consists of 50 wt% plasma atomised (PA) spherical and 50 wt% hydride-dehydride (HDH) irregular-shaped powder with a flowability of 36.5 s, is projected as the raw ...

Breast cancer is characterized by oncobiosis, the abnormal composition of the microbiome in neoplastic diseases. The biosynthetic capacity of the oncobiotic flora in breast cancer is suppressed, as suggested by metagenomic studies. The microbiome synthesizes a set of cytostatic and antimetastatic metabolites that are downregulated in breast cancer, including cadaverine, a microbiome metabolite with cytostatic properties. We set out to assess how the protein expression of constitutive lysine decarboxylase (LdcC), a key enzyme for cadaverine production, changes in the feces of human breast cancer patients (n = 35). We found that the fecal expression of Escherichia coli LdcC is downregulated in lobular cases as compared to invasive carcinoma of no special type (NST) cases. Lobular breast carcinoma is characterized by low or absent expression of E-cadherin. Fecal E. coli LdcC protein expression is downregulated in E-cadherin negative breast cancer cases as compared to positive ones. Receiver operating characteristic (ROC) analysis of LdcC expression in lobular and NST cases revealed that fecal E. coli LdcC protein expression might have predictive values. These data suggest that the oncobiotic transformation of the microbiome indeed leads to the downregulation of the production of cytostatic and antimetastatic metabolites. In E-cadherin negative lobular carcinoma that has a higher potential for metastasis formation, the protein levels of enzymes producing antimetastatic metabolites are downregulated. This finding represents a new route that renders lobular cases permissive for metastasis formation. Furthermore, our findings underline the role of oncobiosis in regulating metastasis formation in breast cancer.

For evolving a surface layer on the X40CrMoV5-1 steel, a plasma-nitridation and PVD coating process was applied. In our experiments, the samples were heat-treated (high-temperature hardening, annealed three times) and surface treatments (plasma-nitridation, PVD coating by TiAlN, duplex surface treating by plasma nitridation and after that, PVD coating TiAlN). After the heat treatments, we performed hardness tests and surface abrasion wear tests. The abrasion wear resistance of the specimens was studied in order to understand the heat treatment effects on abrasion behaviour. It was observed that the heat treatment and surface treatment process greatly influence the tool steel surface hardness and abrasion resistance behaviour. By plasma-nitridation the surface hardness doubled compared to the quenched surface hardness while the PVD coated TiAlN surface layer hardness is more than five times that of the hardened one. There was no relevant difference between the PVD coated (TiAlN) surface hardness and the duplex surface-treated hardness. On the basis of the results of the comparative abrasive wear tests, it can be concluded that the duplex surface treatment resulted in the greatest wear resistance..

In this work, the authors give an overview of the advancement of industrial robots and show the mechanization of welding processes, step by step. As manual welding is a physically exhausting professional work, engineers have sought to improve work conditions since the industrial revolution. Unfortunately, even today, many procedures can only be performed manually. In the welding process, the highest level of mechanization is represented by the use of robotics. The entrance of Robots in the history of welding is recent, though their spread and development are rapid.

BackgroundOsteoclasts play a crucial role in the maintenance, repair, and remodeling of bones of the adult vertebral skeleton due to their bone resorption capability. Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are associated with increased activity of osteoclasts.ObjectivesOur study aimed to investigate the dynamic proteomic changes during osteoclast differentiation in healthy donors, in RA, and PsA.MethodsBlood samples of healthy donors, RA, and PsA patients were collected, and monocytes were isolated and differentiated into osteoclasts in vitro using macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANK-L). Mass spectrometry-based proteomics was used to analyze proteins from cell lysates. The expression changes were analyzed with Gene Set Enrichment Analysis (GSEA).ResultsThe analysis of the proteomic changes revealed that during the differentiation of the human osteoclasts, expression of the proteins involved in metabolic activity, secretory function, and cell polarity is increased; by contrast, signaling pathways involved in the immune functions are downregulated. Interestingly, the differences between cells of healthy donors and RA/PsA patients are most pronounced after the final steps of differentiation to osteoclasts. In addition, both in RA and PsA the differentiation is characterized by decreased metabolic activity, associated with various immune pathway activities; furthermore by accelerated cytokine production in RA.ConclusionsOur results shed light on the characteristic proteomic changes during human osteoclast differentiation and expression differences in RA and PsA, which reveal important pathophysiological insights in both diseases.

Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.

Backround: The number of clinical application of different platelet-rich fibrin (PRF) membranes has increased in regenerative medicine including regenerative dentistry. Intact platelets, leukocytes and stem cells of PRF play a crucial role in the local bone augmentation releasing cytokines and growth factors. An integral part of the postsurgical management is the application of mouthwashes especially chlorhexidine-digluconate, which is recommended in order to prevent postoperative infections. In some cases there is possibility that there is contact between the mouthwash and PRF membrane. The impact of mouthwashes on cell viability of folded F-PRF was tested. Methods: 3 mouthwash brands were tested: Chorsodyl, Listerine 6 in 1 and Elmex Sensitive Plus using MTT viability assay after 30 seconds treatment and 72 hours treatment (twice daily for 30 seconds). The membrane samples were incubated in cell culture conditions. Results: 30 seconds of mouthwash treatment diminished the fresh F-PRF viability significantly by 15-21% depending on the agent. After 72 hours of treatment the viability loss was ~50%. Conclusion: The decreased number of platelets and other blood cells can not launch optimal bone morphogenesis. The MTT assay is cheap, reliable and simple method to assess the platelet and cellular viability and potential regenerative capacity of F-PRF membrane, or any platelet-rich product. The isolation of the PRF membrane from oral liquids and/or application of less aggressive mouthwashes is recommended for at least 5-7 days after PRF surgery.

Breast cancer, the most frequent cancer in women, is characterized by pathological changes to the microbiome of breast tissue, the tumor, the gut, and the urinary tract. Changes to the microbiome are determined by the stage, grade, origin (NST/lobular), and receptor status of the tumor. This year is the 50th anniversary of when Hill and colleagues first showed that changes to the gut microbiome can support breast cancer growth, namely that the oncobiome can reactivate excreted estrogens. The currently available human and murine data suggest that oncobiosis is not a cause of breast cancer, but can support its growth. Furthermore, preexisting dysbiosis and the predisposition to cancer are transplantable. The breast's and breast cancer's inherent microbiome and the gut microbiome promote breast cancer growth by reactivating estrogens, rearranging cancer cell metabolism, bringing about a more inflammatory microenvironment, and reducing the number of tumor-infiltrating lymphocytes. Furthermore, the gut microbiome can produce cytostatic metabolites, the production of which decreases or blunts breast cancer. The role of oncobiosis in the urinary tract is largely uncharted. Oncobiosis in breast cancer supports invasion, metastasis, and recurrence by supporting cellular movement, epithelial-to-mesenchymal transition, cancer stem cell function, and diapedesis. Finally, the oncobiome can modify the pharmacokinetics of chemotherapeutic drugs. The microbiome provides novel leverage on breast cancer that should be exploited for better management of the disease.

The goal of this work was to invent a high energy absorbing composite material. This composite needs to be able to attach on the building's surfaces and increase blast-resistance. In this innovation, the test samples were reinforced with aramidfiber, glass fiber and carbon fiber and tested by Charpy pendulum impact testing machine. During the tests, the aramid and glass fiber reinforced composites showed good resistance and high energy absorption against impact load.

The effects of water/TiO2 Nano-fluid quenching media on microstructure and properties of CK35 steel were analyzed by optical microscopy, X-ray diffraction, Vickers hardness, and tensile tests. The results show that the microstructure of the CK35 steel sample quenched by water/TiO2 Nano-fluid and tempered are the mixture of tempered martensite and retained austenite with best mechanical properties. Whereas the microstructure of the CK35 steel sample quenched by water and tempered is mostly tempered martensite.

Unfortunately, people can’t live in peace in this century: many wars and terrorist attacks have been witnessed even within the last year. In the case of such attacks, both the people and the civil infrastructure is in danger [1-3]. The modern age (infrastructure) provides electrical networks and communication networks for the citizens. Without electricity and/or communications (e.g. the internet), urban life is paralysed. Explosions create heat and shock waves and their effects can potentially damage the wall and cables of a building as changes in the material structure occur. In this article, the authors introduce a blast load effect testing method in an empirical way. The metal microstructure deformation level is measurable by changes in resistance, because resistance is a physical property which depends on the crystal structure of the metal.

(1) Adeno-associated viruses (AAV) are safe and efficient gene therapy vectors with promising results in the treatment of several diseases. Extracellular vesicles (EV) are phospholipid bilayer-surrounded structures carrying several types of lipids, proteins, and nucleic acids with the ability to cross biological barriers. EV-associated AAVs might serve as new and efficient gene therapy vectors considering that they carry the benefits of both AAVs and EVs. (2) We tested vesicle-associated AAVs and vesicles mixed with AAVs on two major cell types of the central nervous system: a neural cell line (N2A) and primary astrocyte cells. (3) In contrast to previously published in vivo observations, the extracellular vesicle packaging did not improve but, in the case of primary astrocyte cells, even inhibited the infection capacity of the AAV particles. The observed effect was not due to the inhibitory effects of the vesicles themselves, since mixing the AAVs with extracellular vesicles did not change the effectiveness. (4) Our results suggest that improvement of the in vivo efficacy of the EV-associated AAV particles is not due to the enhanced interaction between the AAV and the target cells, but most likely to the improved delivery of the AAVs through tissue barriers and to the shielding of AAVs from neutralizing antibodies.

PARP2 is a DNA repair protein. The deletion of PARP2 induces mitochondrial biogenesis and mitochondrial activity by increasing NAD+ levels and inducing SIRT1 activity. We show that the silencing of PARP2 causes mitochondrial fragmentation in myoblasts. We assessed multiple pathways that can lead to mitochondrial fragmentation and ruled out the involvement of mitophagy, the fusion–fission machinery, SIRT1, and mitochondrial unfolded protein response. Nevertheless, mitochondrial fragmentation was reversed by treatment with strong reductants, such as reduced glutathione (GSH), N-acetyl-cysteine (NAC), and a mitochondria-specific antioxidant MitoTEMPO. The effect of MitoTEMPO on mitochondrial morphology indicates the production of reactive oxygen species of mitochondrial origin. Elimination of reactive oxygen species reversed mitochondrial fragmentation in PARP2-silenced cells.

In today’s rapidly changing world, there is an increased need for excellent strategic planning. A firm’s survival may indeed hinge on the firm’s planning process being exemplary. Various aspects of the strategic planning process are under review today as organizations wrestle to compete more effectively. This paper reveals and describes five emerging trends or tools being utilized today by firms to more effectively engage in strategic planning. Specifically, the emerging trends and tools to be discussed in this paper are as follows: 1) Assure vision and mission statements include desired characteristics 2) Perform SWOT (Strengths-Weaknesses-Opportunities-Threats) analysis using AQCD (Actionable, Quantitative, Comparative, and Divisional) factors 3) Utilize varied sources to obtain AQCD information 4) Utilize QSPM (Quantitative Strategic Planning Matrix) analysis to determine the relative attractiveness of alternative strategies 5) Use excel-based software to facilitate and enhance the strategic planning process. The purpose of this paper is to familiarize readers with basic new tools and techniques being used by organizations to effectively develop an improved strategic plan for the firm. JEL Code: M21, O21 ARTICLE IN PRESS!

Simple Summary The aim of our study was to identify metabolites of bacterial origin that play role in the pathogenesis of breast cancer. We identified indoxylsulfate, a metabolite of the amino acid tryptophan, as a metabolite with cytostatic properties on breast cancer cells. Cytostatic properties were dependent on increasing oxidative stress blocking the capacity of cancer cells to migrate, enter blood vessels and to form metastases. Furthermore, indoxylsulfate reduced the proportions of cancer stem cells that are highly resistant to chemotherapy and have vital role in initiating recurrence. We identified that indoxylsulfate exert its effects through the pregnane-X receptor and the aryl-hydrocarbon receptor. The expression of these receptors decrease with the progression of the disease, furthermore, the expression of these receptors is low in cases with poor prognosis. Abstract Changes to bacterial metabolite-elicited signaling, in oncobiosis associated with breast cancer, plays a role in facilitating the progression of the disease. We show that indoxyl-sulfate (IS), a tryptophan metabolite, has cytostatic properties in models of breast cancer. IS supplementation, in concentrations corresponding to the human serum reference range, suppressed tumor infiltration to the surrounding tissues and metastasis formation in a murine model of breast cancer. In cellular models, IS suppressed NRF2 and induced iNOS, leading to induction of oxidative and nitrosative stress, and, consequently, reduction of cell proliferation; enhanced oxidative and nitrosative stress are crucial in the subsequent cytostasis. IS also suppressed epithelial-to-mesenchymal transition vital for suppressing cellular movement and diapedesis. Furthermore, IS rendered cells hypometabolic, leading to a reduction in aldehyde-dehydrogenase positive cells. Pharmacological inhibition of the pregnane-X receptor using CH223191 and the aryl-hydrocarbon receptor using ketoconazole diminished the IS-elicited effects, suggesting that these receptors were the major receptors of IS in these models. Finally, we showed that increased expression of the human enzymes that form IS (Cyp2E1, Sult1A1, and Sult1A2) is associated with better survival in breast cancer, an effect that is lost in triple negative cases. Taken together, IS, similar to indolepropionic acid (another tryptophan metabolite), has cytostatic properties and higher expression of the metabolic machinery responsible for the formation of IS supports survival in breast cancer.

Oncobiotic transformation of the gut microbiome may contribute to the risk of breast cancer. Recent studies have provided evidence that the microbiome secretes cytostatic metabolites that inhibit the proliferation, movement, and metastasis formation of cancer cells. In this study, we show that indolepropionic acid (IPA), a bacterial tryptophan metabolite, has cytostatic properties. IPA selectively targeted breast cancer cells, but it had no effects on non-transformed, primary fibroblasts. In cell-based and animal experiments, we showed that IPA supplementation reduced the proportions of cancer stem cells and the proliferation, movement, and metastasis formation of cancer cells. These were achieved through inhibiting epithelial-to-mesenchymal transition, inducing oxidative and nitrosative stress, and boosting antitumor immune response. Increased oxidative/nitrosative stress was due to the IPA-mediated downregulation of nuclear factor erythroid 2-related factor 2 (NRF2), upregulation of inducible nitric oxide synthase (iNOS), and enhanced mitochondrial reactive species production. Increased oxidative/nitrosative stress led to cytostasis and reductions in cancer cell stem-ness. IPA exerted its effects through aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR) receptors. A higher expression of PXR and AHR supported better survival in human breast cancer patients, highlighting the importance of IPA-elicited pathways in cytostasis in breast cancer. Furthermore, AHR activation and PXR expression related inversely to cancer cell proliferation level and to the stage and grade of the tumor. The fecal microbiome&rsquo, s capacity for IPA biosynthesis was suppressed in women newly diagnosed with breast cancer, especially with stage 0. Bacterial indole biosynthesis showed correlation with lymphocyte infiltration to tumors in humans. Taken together, we found that IPA is a cytostatic bacterial metabolite, the production of which is suppressed in human breast cancer. Bacterial metabolites, among them, IPA, have a pivotal role in regulating the progression but not the initiation of the disease.

Microbes, which live in the human body, affect a large set of pathophysiological processes. Changes in the composition and proportion of the microbiome are associated with metabolic diseases (Fulbright et al., PLoS Pathog 13:e1006480, 2017; Maruvada et al., Cell Host Microbe 22:589-599, 2017), psychiatric disorders (Macfabe, Glob Adv Health Med 2:52-66, 2013; Kundu et al., Cell 171:1481-1493, 2017), and neoplastic diseases (Plottel and Blaser, Cell Host Microbe 10:324-335, 2011; Schwabe and Jobin, Nat Rev Cancer 13:800-812, 2013; Zitvogel et al., Cell 165:276-287, 2016). However, the number of directly tumorigenic bacteria is extremely low. Microbial dysbiosis is connected to cancers of the urinary tract (Yu, Arch Med Sci 11:385-394, 2015), cervix (Chase, Gynecol Oncol 138:190-200, 2015), skin (Yu et al., J Drugs Dermatol 14:461-465, 2015), airways (Gui et al., Genet Mol Res 14:5642-5651, 2015), colon (Garrett, Science 348:80-86, 2015), lymphomas (Yamamoto and Schiestl, Int J Environ Res Public Health 11:9038-9049, 2014; Yamamoto and Schiestl, Cancer J 20:190-194, 2014), prostate (Yu, Arch Med Sci 11:385-394, 2015), and breast (Flores et al., J Transl Med 10:253, 2012; Fuhrman et al., J Clin Endocrinol Metab 99:4632-4640, 2014; Xuan et al., PLoS One 9:e83744, 2014; Goedert et al., J Natl Cancer Inst 107:djv147, 2015; Chan et al., Sci Rep 6:28061, 2016; Hieken et al., Sci Rep 6:30751, 2016; Urbaniak et al., Appl Environ Microbiol 82:5039-5048, 2016; Goedert et al., Br J Cancer 118:471-479, 2018). Microbial dysbiosis can influence organs in direct contact with the microbiome and organs that are located at distant sites of the body. The altered microbiota can lead to a disruption of the mucosal barrier (Plottel and Blaser, Cell Host Microbe 10:324-335, 2011), promote or inhibit tumorigenesis through the modification of immune responses (Kawai and Akira, Int Immunol 21:317-337, 2009; Dapito et al., Cancer Cell 21:504-516, 2012) and microbiome-derived metabolites, such as estrogens (Flores et al., J Transl Med 10:253, 2012; Fuhrman et al., J Clin Endocrinol Metab 99:4632-4640, 2014), secondary bile acids (Rowland, Role of the gut flora in toxicity and cancer, Academic Press, London, p x, 517 p., 1988; Yoshimoto et al., Nature 499:97-101, 2013; Xie et al., Int J Cancer 139:1764-1775, 2016; Shellman et al., Clin Otolaryngol 42:969-973, 2017; Luu et al., Cell Oncol (Dordr) 41:13-24, 2018; Miko et al., Biochim Biophys Acta Bioenerg 1859:958-974, 2018), short-chain fatty acids (Bindels et al., Br J Cancer 107:1337-1344, 2012), lipopolysaccharides (Dapito et al., Cancer Cell 21:504-516, 2012), and genotoxins (Fulbright et al., PLoS Pathog 13:e1006480, 2017). Thus, altered gut microbiota may change the efficacy of chemotherapy and radiation therapy (McCarron et al., Br J Biomed Sci 69:14-17, 2012; Viaud et al., Science 342:971-976, 2013; Montassier et al., Aliment Pharmacol Ther 42:515-528, 2015; Buchta Rosean et al., Adv Cancer Res 143:255-294, 2019). Taken together, microbial dysbiosis has intricate connections with neoplastic diseases; hereby, we aim to highlight the major contact routes.

Significance: Nuclear factor erythroid 2 (NFE2)-related factor 2 (NFE2L2, or NRF2) is a transcription factor predominantly affecting the expression of antioxidant genes. NRF2 plays a significant role in the control of redox balance, which is crucial in cancer cells. NRF2 activation regulates numerous cancer hallmarks, including metabolism, cancer stem cell characteristics, tumor aggressiveness, invasion, and metastasis formation. We review the molecular characteristics of the NRF2 pathway and discuss its interactions with the cancer hallmarks previously listed. Recent Advances: The noncanonical activation of NRF2 was recently discovered, and members of this pathway are involved in carcinogenesis. Further, cancer-related changes (e.g., metabolic flexibility) that support cancer progression were found to be redox- and NRF2 dependent. Critical Issues: NRF2 undergoes Janus-faced behavior in cancers. The pro- or antineoplastic effects of NRF2 are context dependent and essentially based on the specific molecular characteristics of the cancer in question. Therefore, systematic investigation of NRF2 signaling is necessary to clarify its role in cancer etiology. The biggest challenge in the NRF2 field is to determine which cancers can be targeted for better clinical outcomes. Further, large-scale genomic and transcriptomic studies are missing to correlate the clinical outcome with the activity of the NRF2 system. Future Directions: To exploit NRF2 in a clinical setting in the future, the druggable members of the NRF2 pathway should be identified. In addition, it will be important to study how the modulation of the NRF2 system interferes with cytostatic drugs and their combinations.

In this study we performed the comprehensive pharmacological analysis of two stereoisomers of 4-chloro-meta-cresol (4CMC), a popular ryanodine receptor (RyR) agonist used in muscle research. Experiments investigating the Ca2+-releasing action of the isomers demonstrated that the most potent isomer was 4-chloro-orto-cresol (4COC) (EC50 = 55 ± 14 μM), although 3-chloro-para-cresol (3CPC) was more effective, as it was able to induce higher magnitude of Ca2+ flux from isolated terminal cisterna vesicles. Nevertheless, 3CPC stimulated the hydrolytic activity of the sarcoplasmic reticulum ATP-ase (SERCA) with an EC50 of 91 ± 17 μM, while 4COC affected SERCA only in the millimolar range (IC50 = 1370 ± 88 μM). IC50 of 4CMC for SERCA pump was 167 ± 8 μM, indicating that 4CMC is not a specific RyR agonist either, as it activated RyR in a similar concentration (EC50 = 121 ± 20 μM). Our data suggest that the use of 4COC might be more beneficial than 4CMC in experiments, when Ca2+ release should be triggered through RyRs without influencing SERCA activity.

In the cities, civilization use many electrical wiring and network cables. The explosion-established high rate energy (as an effect of terrorist attacks) can cause damage in the electrical and communication system. The explosives are different and affect different damage. The wires conduct electricity and the other group the network cables support the communication. Both of them are very important in our urban structure. Without electricity and/or communication (internet), urban life is frozen and it influences the soft targets protections. The metals conductivity, resistance and mechanical properties as a function of the blast attacks can change. These properties are important to ensure continuous service. The goal of the paper is to study the copper cables mechanical and physical properties changing under the blast load.

The focus target of our century and even of all centuries in the history is the security. Every state wants to guard their own functionality and citizens. The treasure of the nations are firstly peoples (soft target) and after all, buildings and assets.