Berbamine targets cancer stem cells and reverses cabazitaxel resistance via inhibiting IGF2BP1 and p‐STAT3 in prostate cancer

Background Cancer stem cells (CSCs) are a small subpopulation of tumor cells with the capability of self-renewal and drug resistance, leading to tumor progression and disease relapse. Our study aimed to investigate the antitumor effect of berbamine, extracted from berberis amurensis, on prostate CSCs. Methods Sphere formation was used to collect prostate CSCs. The viability, proliferation, invasion, migration, and apoptosis assays were used to evaluate the antitumor effect of berbamine on prostate CSCs. Prostate CSC markers were analyzed by flow cytometry and qRT-PCR. Small RNA sequencing analysis was conducted to analyse miRNAs. Exosomes were extracted using the ExoQuick-TC kit and verified by testing exosomal markers using western blot. Results Berbamine targets prostate CSCs. Additionally, berbamine enhanced the antitumor effect of cabazitaxel, a second-line chemotherapeutic drug for advanced prostate cancer, and re-sensitized Cabazitaxel-resistant PCa cells (CabaR-DU145) to cabazitaxel by inhibiting ABCG2, CXCR4, IGF2BP1, and p-STAT3. Berbamine enhanced the expression of let-7 miRNA family and miR-26b and influenced the downstream targets IGF2BP1 and p-STAT3, respectively. Silencing CXCR4 and ABCG2 downregulated the expression of IGF2BP1 and p-STAT3, respectively. Importantly, berbamine enhanced also levels of exosomal let-7 family and miR-26b, suggesting that berbamine possibly influences the expression of let-7 family and miR-26b through exosome delivery. Exosomes derived from berbamine-treated CabaR-DU145 cells re-sensitized the cells to cabazitaxel. Conclusion Berbamine enhanced the toxic activity of cabazitaxel and reversed cabazitaxel resistance potentially through CXCR4/exosomal let-7/IGF2BP1 and ABCG2/exosomal miR-26b/p-STAT3 axes

Frontiers: The Interplay of User-Generated Content, Content Industry Revenues, and Platform Regulation: Quasi-Experimental Evidence from YouTube

An ongoing debate among firms, rightsholders, particularly in the music industry, and policymakers in the United States and the European Union concerns potential changes to the regulation of user-generated content (UGC) video streaming platforms (e.g., YouTube). Currently, safe harbor provisions protect platforms from liability for copyright-infringing content uploaded by users, and requirements for compensating rightsholders for UGC are weak, resulting in comparatively low payouts. At the same time, it is unclear how a change in these regulations would affect consumer demand for this content on other platforms with higher payouts (e.g., Spotify), that is, whether UGC platforms stimulate or displace demand on other platforms. We study a quasi-experiment that occurred when numerous songs became available as UGC on YouTube after an agreement between YouTube and the German royalty collecting society. Our analysis of an unprecedented data set covering 600,000 songs by 38,000 artists reveals an intriguing finding: Although UGC availability stimulates demand in other streaming channels for most songs, cannibalization occurs for recent releases and hit releases, turning the overall revenue effect negative. We discuss how policymakers can use these findings to understand the implications of changes in regulation, and how labels and artists can decide which content to block or allow on UGC platforms

All Bark and No Bite?

Organizations are increasingly installing Chief Digital Officers (CDOs) to cope with the challenges of digital transformation (DT). Due to DT’s cross-functional nature and the far-reaching tasks involved, CDOs must wield sufficient influence to manage DT effectively. Thus far, we lack a profound understanding of how CDOs’ power is composed. To address this research gap, we conducted a multiple-case study drawing on 25 interviews across six case companies. We identify several drivers of CDOs’ power, both in terms of formal and informal power types. Particularly, we demonstrate that CDOs’ power depends not only on organizational contingencies but also on the managers’ personal characteristics. We contribute to literature by adding a power notion to discussions on DT in general and CDOs specifically. Further, we sensitize practitioners to establish the CDO role in a way that is endowed with sufficient power and shed light on how CDOs can increase their power base

Validation of an open source, remote web‐based eye‐tracking method (WebGazer) for research in early childhood

Measuring eye movements remotely via the participant's webcam promises to be an attractive methodological addition to in-person eye-tracking in the lab. However, there is a lack of systematic research comparing remote web-based eye-tracking with in-lab eye-tracking in young children. We report a multi-lab study that compared these two measures in an anticipatory looking task with toddlers using WebGazer.js and jsPsych. Results of our remotely tested sample of 18-27-month-old toddlers (N = 125) revealed that web-based eye-tracking successfully captured goal-based action predictions, although the proportion of the goal-directed anticipatory looking was lower compared to the in-lab sample (N = 70). As expected, attrition rate was substantially higher in the web-based (42%) than the in-lab sample (10%). Excluding trials based on visual inspection of the match of time-locked gaze coordinates and the participant's webcam video overlayed on the stimuli was an important preprocessing step to reduce noise in the data. We discuss the use of this remote web-based method in comparison with other current methodological innovations. Our study demonstrates that remote web-based eye-tracking can be a useful tool for testing toddlers, facilitating recruitment of larger and more diverse samples; a caveat to consider is the larger drop-out rate

Prescribing cascades in ambulatory care: A structured synthesis of evidence

The strength of evidence for specific ambulatory care prescribing cascades, in which a marker drug is used to treat an adverse event caused by an index drug, has not been well characterized. To perform a structured, systematic, and transparent review of the evidence supporting ambulatory care prescribing cascades. Ninety-four potential prescribing cascades identified through a previously published systematic review. Systematic search of the literature to further characterize prescribing cascades. (1) Grading of evidence based on observational studies investigating associations between index and marker drugs, including: Level I—strong evidence [i.e. multiple high-quality studies]; Level II—moderate evidence [i.e. single high-quality study]; Level III—fair evidence [no high-quality studies but one or more moderate-quality studies]; and Level IV—poor evidence [other]. (2) Listing of the adverse event associated with the index drug in the product's United States Food and Drug Administration (FDA) label. (3) Synthesis of the evidence supporting mechanisms linking index drugs and associated adverse events. Of 99 potential cascades, 94 were supported by one or more confirmatory observational studies and were therefore included in this review. The 94 cascades related to 30 types of adverse drug reactions affecting 10 different anatomic/physiologic systems and were investigated by a total of 88 confirmatory studies, including prescription sequential symmetry analysis (n = 51), cohort (n = 30), and case–control (n = 7) studies. Overall, the evidence from observational studies was strong for 18 (19.1%) prescribing cascades, moderate for 61 (64.9%), fair for 13 (13.8%), and poor for 2 (2.1%). Although the evidence supporting mechanisms that link index drugs and associated adverse events was variable, FDA labels included information about the adverse event associated with the index drug for most (n = 86) but not all of the 94 prescribing cascades. Although we identified 18 of 94 prescribing cascades supported by strong clinical evidence and most adverse events associated with index drugs are included in FDA label, the evidentiary basis for prescribing cascades varies, with many requiring further evidence of clinical relevance

Wie kommt der Religionsunterricht zu seinen Inhalten? Erkundungen zwischen Fridays for Future, Abraham und Sühneopfertheologie

»Wie kommen die Inhalte in den Religionsunterricht?« Diese Frage führt direkt ins Zentrum der Religionspädagogik. Aktuelle Herausforderungen für religiöse Bildung wie Säkularisierung und Pluralisierung sowie neue Anforderungen, z.B. im Zuge von Kompetenzorientierung und Digitalisierung, stellen die Frage nach den Inhalten neu und vehement. Die Beiträger*innen bringen aus historischer, systematischer, normativer und empirischer Perspektive diesen Diskurs voran. Damit liefern sie unverzichtbare Grundlagen für alle, die für die Auswahl und Didaktisierung religionsunterrichtlicher Inhalte in Theorie und Praxis verantwortlich sind

Power to all or few People? An Exploration of Power Dynamics in Holocrazy

Power is key to all organizing. It allows actors to perform actions, make decisions and assign tasks to others. In bureaucratic organizations power is mainly associated with the position that the actor holds. Because actors compete for power, change their position within an organization or leave an organization, power is dynamically changing. We refer to these changes in power as power dynamics. Many New Forms of Organizing, such as Holacracy, claim that individuals have more decision-making capacity, i.e., that power is more equally distributed within the organization. In this paper, we use a unique dataset from a holacratic organization to empirically examine how power dynamics in Holacracy evolve over time. In particular, we use temporal network analysis to reconstruct and contrast two related networks that capture information on how decisions in Holacracy are made. Our findings indicate that also in Holacracy power is not equally distributed, but that few individuals hold most power

Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function

Objective Debate surrounds the role of chronic pain as a risk factor for cognitive decline and dementia. This study aimed at examining the association of chronic pain with biomarkers of neurodegeneration using data from the Alzheimer's Disease Neuroimaging Initiative. Methods Participants were classified using the ATN (amyloid, tau, neurodegeneration) classification. Chronic pain was defined as persistent or recurrent pain reported at baseline. For each ATN group, analysis of covariance models identified differences in cerebrospinal fluid (CSF) levels of amyloid β1–42, phosphorylated tau 181 (ptau181), total tau (t-tau), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and cognitive function between chronic pain states. Differences in CSF levels of inflammatory markers between chronic pain states were further analyzed. Linear mixed effect models examined longitudinal changes. Results The study included 995 individuals, with 605 (60.81%) reporting chronic pain at baseline. At baseline, individuals with suspected non-Alzheimer pathophysiology and chronic pain showed increased CSF levels of t-tau and sTREM2. Chronic pain was associated with increased tumor necrosis factor α levels, irrespective of the ATN group. Longitudinally, an increase in ptau181 CSF levels was observed in chronic pain patients with negative amyloid and neurodegeneration markers. Amyloid-positive and neurodegeneration-negative chronic pain patients showed higher memory function cross-sectionally. No significant longitudinal decline in cognitive function was observed for any ATN group. Interpretation Our study suggests that chronic pain induces neuronal damage and microglial activation in particular subgroups of patients along the AD spectrum. Further studies are needed to confirm these findings. ANN NEUROL 2024;95:195–20