NRF2-ome: An integrated web resource to discover protein interaction and regulatory networks of NRF2

NRF2 is the master transcriptional regulator of oxidative and xenobiotic stress responses. NRF2 has important roles in carcinogenesis, inflammation, and neurodegenerative diseases. We developed an online resource, NRF2-ome, to provide an integrated and systems-level database for NRF2. The database contains manually curated and predicted interactions of NRF2 as well as data from external interaction databases. We integrated NRF2 interactome with NRF2 target genes, NRF2 regulating TFs, and miRNAs. We connected NRF2-ome to signaling pathways to allow mapping upstream NRF2 regulatory components that could directly or indirectly influence NRF2 activity totaling 35,967 protein-protein and signaling interactions. The user-friendly website allows researchers without computational background to search, browse, and download the database. The database can be downloaded in SQL, CSV, BioPAX, SBML, PSI-MI, and in a Cytoscape CYS file formats. We illustrated the applicability of the website by suggesting a posttranscriptional negative feedback of NRF2 by MAFG protein and raised the possibility of a connection between NRF2 and the JAK/STAT pathway through STAT1 and STAT3. NRF2-ome can also be used as an evaluation tool to help researchers and drug developers to understand the hidden regulatory mechanisms in the complex network of NRF2. © 2013 Dénes Türei et al

Starvation-response may not involve Atg1-dependent autophagy induction in non-unikont parasites

Autophagy, the lysosome-mediated self-degradation process, is implicated in survival during starvation in yeast, Dictyostelium and animals. In these eukaryotic taxa (collectively called Unikonts), autophagy is induced primarily through the Atg1/ULK1 complex in response to nutrient depletion. Autophagy has also been well-studied in non-unikont parasites, such as Trypanosoma and Plasmodium, and found important in their life-cycle transitions. However, how autophagy is induced in non-unikonts remains largely unrevealed. Using a bioinformatics approach, we examined the presence of Atg1 and of its complex in the genomes of 40 non-unikonts. We found that these genomes do not encode typical Atg1 proteins: BLAST and HMMER queries matched only with the kinase domain of Atg1, while other segments responsible for regulation and protein-binding were missing. Non-unikonts also lacked other components of the Atg1-inducing complex. Orthologs of an alternative autophagy inducer, Atg6 were found only in the half of the species, indicating that the other half may possess other inducing mechanisms. As key autophagy genes have differential expression patterns during life-cycle, we raise the possibility that autophagy in these protists is induced mainly at the post-transcriptional level. Understanding Atg1-independent autophagy induction mechanisms in these parasites may lead to novel pharmacological interventions, not affecting human Atg1-dependent autophagy

A De Quervain-féle tendinopathia kezelése konzervatív módszerekkel = Treatment of De Quervain’s tendinopathy with conservative methods

Absztrakt: Bevezetés: A De Quervain-féle tendinopathia a csukló-kéz régióját érintő betegség. A hüvelykujj mozgatása fájdalmassá válik, a kéz funkciója jelentősen romlik. A betegség a legújabb kutatások szerint inkább degeneratív, semmint gyulladásos eredetű. Első lépésként a kéz sínezése, nemszteroid gyulladáscsökkentő szerek és különböző fizikoterápiás kezelések alkalmazása javasolt. Hatástalanságuk esetén további lehetőség az ínhüvelybe fecskendezett szteroidinjekció és a műtéti úton végzett ínhüvelybemetszés. Célkitűzés: Kutatásunkban megvizsgáltuk, hogy az excentrikus tréninggel kibővített konzervatív kezelés megfelelő alternatíváját nyújthatja-e a jelenleg elfogadott kezelési lehetőségeknek. Módszer: Az excentrikus tréning 8 hétig tartott, melyet indokolt esetben 12 hetesre bővítettünk. A betegek (n = 9) a betanítást követően naponta többször végezték a tréninget, amit a heti találkozók alkalmával kontrolláltunk. Az 1., a 8., valamint a 12. heti találkozó során az inspekciót követően mértük az ízületi mozgástartományt, az izomerőt, a fájdalmas régiók számát, illetve elvégeztük a ’Numeric Pain Rating Scale’, a ’Quick Disabilities of the Arm, Shoulder and Hand’, valamint a ’Patient-Rated Wrist Evaluation’ kérdőívek felvételét. A méréseket páros mintás t-teszttel és ismételt méréses varianciaanalízissel elemeztük. Az elemzéseket IBM SPSS Statistics 25.0 és Microsoft Office Excel Professional Plus 2016 programmal végeztük; p<0,05 esetén tekintettük statisztikailag szignifikánsnak eredményeinket. Eredmények: Szignifikáns javulást mértünk a fájdalom intenzitása (’Numeric Pain Rating Scale’ p = 0,005, n = 9) és a kéz, valamint a csukló funkciója terén (’Quick Disabilities of the Arm, Shoulder and Hand Outcome Measure’ kérdőív 1. rész p<0,001, 2. rész p<0,001, ’Patient-Rated Wrist Evaluation’ kérdőív p<0,001; n = 9). Következtetés: Eredményeink alapján megfelelő betegbeválasztás mellett az excentrikus tréninggel kibővített konzervatív kezelés valós alternatívája lehet a jelenleg alkalmazott kezeléseknek. Orv Hetil. 2020; 161(11): 419–424. | Abstract: Introduction: De Quervain’s tendinopathy affects the region of the wrist and the hand. Thumb motion becomes painful. This illness is caused by a degenerative process rather than inflammation. Primary treatment methods are splinting, taking non-steroid anti-inflammatory drugs and different physical therapeutic modalities, administration of a steroid injection into the tendon sheath or surgical release of the tendon sheath may be performed. Aim: The aim of the present study was to investigate whether conservative treatment complemented by eccentric training could provide an adequate alternative to the currently accepted treatment options. Method: The eccentric training lasted for 8 weeks (if necessary for 12 weeks). Following the introduction to exercises, patients (n = 9) repeated the training several times a day, which was controlled during weekly meetings. At the 1st, 8th and 12th meetings, inspection and the following measurements were performed: range of motion, muscle strength, evaluation and number of painful regions including the completion of patient questionnaires. Data were analysed with paired samples t-tests and repeated measures ANOVA. IBM SPSS Statistics 25.0 and Microsoft Office Excel Professional Plus 2016 programs were used. Results were regarded significant at level of p<0.05. Results: Significant improvements were found in the intensity of pain (Numeric Pain Rating Scale p = 0.005, n = 9) and in the functionality of the hand and wrist (Quick Disabilities of the Arm, Shoulder and Hand questionnaire part 1. p<0.001, part 2. p<0.001, Patient-Rated Wrist Evaluation questionnaire p<0.001; n = 9). Conclusion: With careful patient selection, conservative treatment complemented by eccentric training could be an alternative to current treatment options. Orv Hetil. 2020; 161(11): 419–424

Súlypont stabilizálás meghatározása 16-18 éves korú lányoknál és fiúknál - előtanulmány a normál tartományok meghatározásához = Determining stability of center of gravity in 16-18 year old girls and boys – a pilot study to determine the normal range

Az egyensúlyozás az ember legtermészetesebb mozgástevékenysége, melyben a súlypont stabilitás meghatározó. Az egyensúlyozó képesség jellemzésére a klinikumban gyakran alkalmazott, megfigyelésen alapuló szubjektív vizsgálati módszer a statikus Romberg és a dinamikus Fukuda (Unterberger) teszt, melyek a test elmozdulását és kilengését vizsgálják. Ultrahang alapú, számítógép vezérlésű, kraniokorpográfiás (UH-COM-CCG) mérőrendszer segítségével meghatároztuk az egyensúlyozást igénylő mozgás és állás közben kivitelezett testtartás, fejhelyzet, mozgáskoordináció és az egyensúlyi állapot egymással szorosan összefüggő paramétereinek normál tartományát 16-18 éves egészséges fiatalok körében. Előtanulmányunk a normál tartományok meghatározásának alkalmazott eljárásával hozzájárulhat ahhoz, hogy a további kutatások során reprezentatív mintán határozzuk meg a normál tartományokat. Ezen tartományok meghatározása hiátuspótló, mivel a klinikumban használt statikus és dinamikus súlypontvizsgálati tesztekhez normálnak tekinthető tartományok korosztály-specifikusan a szakirodalomban nem lelhetők fel. A diagnosztika objektivizálásával egyszerű vizsgálati lehetőség nyílik nemcsak enyhébb és súlyosabb eltérések kimutatására, a részfunkció zavarok véleményezésére, diagnózisok alátámasztására, a terápia megtervezésére és eredményességének vizsgálatára, hanem a sport és az egészségmegőrzés területén állapotfelmérésre, az egyes sportágak tulajdonságaiból adódó egyoldalú terhelések miatt kialakuló eltérések kimutatására is. Ismételt vizsgálatokkal nyomon követhető a törzs dinamikus stabilitásának változása, és így az egyes edzésmódok hatékonyságának elemzésére is lehetőség nyílik. Az egyéni eredmények értékelésével nő a személyre szabott fejlesztési tervek kidolgozásának esélye. Balancing is the most natural movement activity, in which the stability of the centre of gravity is decisive. The observational subject-based test methods often used in the clinic to characterize the balancing ability (the static Romberg and the dynamic Fukuda (Unterberger) tests), which examine the displacement and oscillation of the body. Using an ultrasound-based, computer-controlled, craniocorpographic (UH-COM-CCG) measurement system, we determined the normal range of closely related parameters of movement and standing posture, head position, movement coordination, and steady state in 16–18-year-old healthy youth. Our applied method of identifying the normal ranges can contribute to determination of normal ranges on a representative sample in future esearch. Defining these ranges can fill the gap for static and dynamic centre of gravity tests in the clinic because there are no age-specific normal ranges in literature. By objectifying the diagnostics, it is possible to examine not only milder and more serious differences, to evaluate partial dysfunction, to support diagnoses, to plan therapy and to examine its effectiveness, but it is also applicable for condition assessment in the field of sports and health care and to identify alterations due to unilateral loads in each sport. Repeated examinations can be used to monitor changes in dynamic stability of trunk, which may make it possible to analyse effectiveness of each training modes. Evaluating individual outcomes increases chances of developing personalized development plans

Complex regulation of autophagy in cancer - integrated approaches to discover the networks that hold a double-edged sword.

Autophagy, a highly regulated self-degradation process of eukaryotic cells, is a context-dependent tumor-suppressing mechanism that can also promote tumor cell survival upon stress and treatment resistance. Because of this ambiguity, autophagy is considered as a double-edged sword in oncology, making anti-cancer therapeutic approaches highly challenging. In this review, we present how systems-level knowledge on autophagy regulation can help to develop new strategies and efficiently select novel anti-cancer drug targets. We focus on the protein interactors and transcriptional/post-transcriptional regulators of autophagy as the protein and regulatory networks significantly influence the activity of core autophagy proteins during tumor progression. We list several network resources to identify interactors and regulators of autophagy proteins. As in silico analysis of such networks often necessitates experimental validation, we briefly summarize tractable model organisms to examine the role of autophagy in cancer. We also discuss fluorescence techniques for high-throughput monitoring of autophagy in humans. Finally, the challenges of pharmacological modulation of autophagy are reviewed. We suggest network-based concepts to overcome these difficulties. We point out that a context-dependent modulation of autophagy would be favored in anti-cancer therapy, where autophagy is stimulated in normal cells, while inhibited only in stressed cancer cells. To achieve this goal, we introduce the concept of regulo-network drugs targeting specific transcription factors or miRNA families identified with network analysis. The effect of regulo-network drugs propagates indirectly through transcriptional or post-transcriptional regulation of autophagy proteins, and, as a multi-directional intervention tool, they can both activate and inhibit specific proteins in the same time. The future identification and validation of such regulo-network drug targets may serve as novel intervention points, where autophagy can be effectively modulated in cancer therapy

Complex regulation of autophagy in cancer - integrated approaches to discover the networks that hold a double-edged sword

Autophagy, a highly regulated self-degradation process of eukaryotic cells, is a context-dependent tumor-suppressing mechanism that can also promote tumor cell survival upon stress and treatment resistance. Because of this ambiguity, autophagy is considered as a double-edged sword in oncology, making anti-cancer therapeutic approaches highly challenging. In this review, we present how systems-level knowledge on autophagy regulation can help to develop new strategies and efficiently select novel anti-cancer drug targets. We focus on the protein interactors and transcriptional/post-transcriptional regulators of autophagy as the protein and regulatory networks significantly influence the activity of core autophagy proteins during tumor progression. We list several network resources to identify interactors and regulators of autophagy proteins. As in silico analysis of such networks often necessitates experimental validation, we briefly summarize tractable model organisms to examine the role of autophagy in cancer. We also discuss fluorescence techniques for high-throughput monitoring of autophagy in humans. Finally, the challenges of pharmacological modulation of autophagy are reviewed. We suggest network-based concepts to overcome these difficulties. We point out that a context-dependent modulation of autophagy would be favored in anti-cancer therapy, where autophagy is stimulated in normal cells, while inhibited only in stressed cancer cells. To achieve this goal, we introduce the concept of regulo-network drugs targeting specific transcription factors or miRNA families identified with network analysis. The effect of regulo-network drugs propagates indirectly through transcriptional or post-transcriptional regulation of autophagy proteins, and, as a multi-directional intervention tool, they can both activate and inhibit specific proteins in the same time. The future identification and validation of such regulo-network drug targets may serve as novel intervention points, where autophagy can be effectively modulated in cancer therapy

No Association between Gastrointestinal Rebleeding and DOAC Therapy Resumption: A Systematic Review and Meta-Analysis

Background: There are recommendations for anticoagulation resumption after gastrointestinal bleeding (GIB), although data addressing this topic by direct oral anticoagulants (DOACs)-treated patients is lacking. We aim to determine the safety and efficacy of restarting DOACs after GIB. Methods: Studies that reported rebleeding, thromboembolic events, and mortality after restarting or withholding DOACs were selected. The systematic research was conducted in five databases (MEDLINE, EMBASE, CENTRAL, Web of Science, and Scopus). The random effect model was implemented to calculate the pooled odds ratio (OR). The ROBINS-I tool was used for risk of bias assessment, and the certainty of the evidence was evaluated with the GRADE approach. Results: Four retrospective cohort studies (1722 patients) were included in the meta-analysis. We did not find a significant increase in the risk of rebleeding in patients restarting DOACs after index GIB (OR = 1.12; 95% CI: 0.74–1.68). The outcomes of thromboembolic events and mortality data were not suitable for meta-analytic calculations. Single studies did not show statistically significant differences. Data quality assessment showed a serious overall risk of bias and very low quality of evidence (GRADE D). Conclusion: DOAC resumption after a GIB episode may not elevate the risk of rebleeding. However, the need for high-quality randomized clinical trials is crucial