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New platinum derivatives selectively cause double-strand DNA breaks and death in naïve and cisplatin-resistant cholangiocarcinomas
Get PDFBackground & Aims:
Patients with cholangiocarcinoma (CCA) have poor prognosis. Current cisplatin-based first-line chemotherapy offers limited survival benefit. Cisplatin induces single-strand DNA breaks, activating DNA repair mechanisms that diminish its effectiveness. Here, we present the design, chemical synthesis, and therapeutic evaluation of a new generation of chemotherapeutic agents (Aurkines) with unique polyelectrophilic properties. These agents cause a high frequency of double-strand DNA breaks, bypassing DNA repair, and promoting cancer cell death.
Methods:
Two novel compounds, Aurkine 16 and Aurkine 18, were designed and evaluated for their antitumor effects in both naïve and cisplatin-resistant CCA cells, cancer-associated fibroblasts, healthy cholangiocytes, and in vivo models.
Results:
Aurkines effectively induced double-strand DNA breaks, leading to increased DNA damage and elevated levels of reactive oxygen species, resulting in greater cytotoxicity than cisplatin in CCA cells. Phosphoproteomic and molecular analysis revealed that cisplatin activates DNA repair pathways, while Aurkines primarily induce apoptosis. Importantly, Aurkines also triggered apoptosis in cisplatin-resistant CCA cells and cancer-associated fibroblasts without harming healthy cholangiocytes. Additionally, Aurkines demonstrated cytotoxicity in other cisplatin-resistant cancers, such as breast and ovarian cancer. This tumor selectivity results from reduced uptake, increased efflux, and compact chromatin structure in normal cells, limiting Aurkine-DNA interactions. In vivo, Aurkines inhibited the growth of subcutaneous naïve and cisplatin-resistant CCA tumors, as well as orthotopic tumors in immunocompetent mice, promoting antitumor immune cell recruitment without any adverse events. Transport studies revealed that Aurkines were selectively taken up by OCT1, OCT3, CTR1, and OATP1A2, whereas only CTR1 transported cisplatin.
Conclusions:
Aurkines represent promising therapeutic drugs for both naïve and cisplatin-resistant cancers due to their unique polyelectrophilic properties and selective targeting of malignant cells
Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia
Get PDFCasitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase critical for negatively regulating receptor protein tyrosine kinases (RTKs). Deleterious CBL mutants lose E3 activity, but act as adaptors that gain function to cause myeloproliferative neoplasms. Currently, there is no targeted treatment available for patients with CBL mutant-dependent disorders. By combining phage-display technology and structure-based optimization, we discovered CBLock, a nanomolar affinity peptide inhibitor, that binds the substrate-binding site of CBL's tyrosine kinase binding domain (TKBD). CBLock disrupts the interaction between CBL mutants and RTKs, thereby impairing RTK-mediated priming of adaptor function of CBL mutants and downstream signaling. Notably, CBLock binds TKBD without inducing conformational changes, thereby preserving its ligand-free native conformation. In contrast, when CBL binds RTK substrates, TKBD undergoes a conformational change. Maintaining the native CBL TKBD conformation was crucial for CBLock to inhibit proliferation, induce cell-cycle arrest, and promote apoptosis in leukemia cells harboring CBL mutations. In a mouse xenograft model of acute myeloid leukemia (AML), CBLock reduced tumor burden and improved survival rate. Moreover, CBLock inhibited the proliferation of cells derived from patients with CBL mutations. Therefore, inhibiting CBL TKBD in its native state presents a promising therapeutic opportunity in targeting mutant CBL-dependent leukemia
Spironolactone versus placebo in patients undergoing maintenance dialysis (ACHIEVE): an international, parallel-group, randomised controlled trial
No full textBackground:
Patients undergoing maintenance dialysis for kidney failure are at substantial risk of cardiovascular morbidity and mortality. We aimed to establish if spironolactone reduces heart failure and cardiovascular deaths in these patients.
Methods:
ACHIEVE was an international, parallel-group, randomised controlled trial done in 143 dialysis programmes in 12 countries. Patients were aged 45 years or older, or aged 18 years or older with a history of diabetes, and were receiving maintenance dialysis for kidney failure for at least 3 months at the time of recruitment. Patients who were able to tolerate and adhere to spironolactone 25 mg daily orally during an open-label run-in were randomly assigned (1:1) to continue spironolactone or matching placebo, using a central computerised block randomisation system (block sizes of 4) stratified by centre. Participants, health-care providers, and those assessing outcomes were masked to group assignment. The primary outcome was a composite of cardiovascular mortality or hospitalisation for heart failure analysed as time-to-event in all randomly assigned participants. The trial was registered at ClinicalTrials.gov, NCT03020303.
Findings:
After a planned interim analysis of 75% of the expected primary outcome events, the external safety and efficacy monitoring committee recommended the trial be stopped early for futility. From Sept 19, 2017, to Oct 31, 2024, 3689 patients were screened for inclusion, 3565 of whom were enrolled in the open-label run-in phase, and 2538 were randomly assigned to spironolactone (n=1260) or placebo (n=1278). 931 (36·7%) participants were female and 1607 (63·3%) were male. Median follow-up was 1·8 years (IQR 0·85–3·35). The composite primary outcome occurred in 258 participants (10·46 events per 100 patient-years) in the spironolactone group and in 276 participants (11·33 per 100 patient-years) in the placebo group (hazard ratio [HR] 0·92 [95% CI 0·78–1·09]; p=0·35). Death from any cause was similar between groups (HR 0·95 [0·83–1·09]) as was hospitalisation for any cause (HR 0·96 [0·87–1·06]).
Interpretation:
Among patients receiving maintenance dialysis, spironolactone 25 mg daily orally did not reduce the composite outcome of cardiovascular mortality and hospitalisation due to heart failure compared with placebo. This trial did not identify a benefit of initiating spironolactone in patients receiving maintenance dialysis. Future research should consider alternatives to steroidal mineralocorticoid receptor antagonism to reduce cardiovascular morbidity and mortality in patients receiving maintenance haemodialysis
An approach to using stranding data to monitor cetacean population trends and guide conservation strategies
Get PDFGrowing anthropogenic pressures increasingly impact marine wildlife, with cetaceans being particularly vulnerable to cumulative effects of stressors due to their position as top predators. As sensors and sentinels of ocean health, cetaceans offer critical insight into known and emerging threats to marine ecosystems. Stranding schemes provide a cost-effective means to assess mortality rates and population demographics, offering insights that are often challenging to obtain through live monitoring. Using a 30-year dataset from the Scottish Marine Animal Stranding Scheme (SMASS) we demonstrate how opportunistically obtained stranding data can be used to monitor populations and guide conservation strategies. Species were clustered into broad ecological groups - baleen whales, short-beaked common dolphins, deep divers, harbour porpoises and pelagic dolphins - for spatiotemporal analysis of stranding patterns. All groups showed increases in annual stranding rates over the study period, with common dolphins and baleen whales exhibiting exponential increases, suggesting these species may be facing heightened pressures. Distinct seasonal and spatial trends were detected, with harbour porpoises predominantly stranding on the east coast and other groups clustering to Scotland’s west coast. Identifying these trends helps focus surveillance and mitigation efforts, underscoring the importance of this approach for monitoring vulnerable species
Projected climate regime over Pakistan and its implications for hydrology in the Hunza River Basin using CMIP6 GCMs
No full textThe Hunza River Basin (HRB), located in the Upper Indus Basin of Pakistan, is highly vulnerable to climate change because its streamflow primarily depends on snow and glacier melt. This study evaluates the impacts of climate change on the HRB’s water resources using Global Climate Models (GCMs) from Coupled Model Intercomarision Project phase 6 (CMIP6) and a state-of-the-art hydrological model (HBV-light). The HBV-light model incorporates a mass-conserving ∆h parameterization, which simulates changes in glacier geometry over time and is well-suited for modeling the impacts of climate change in glacier-dominated basins such as the HRB. This study has two main objectives: (1) to conduct a comprehensive evaluation of eight CMIP6 GCMs and their multi-model ensemble mean across Pakistan, and (2) to assess projected hydroclimatic changes in the HRB under future climate scenarios. Climate data from the GCMs were statistically downscaled using the Python-based software pyClim-SDM, which features a user-friendly graphical interface for generating custom downscaled scenarios. The downscaled data were then input into the HBV-light model to simulate future water availability. Results reveal a consistent increase in mean temperature and variable precipitation patterns under the SSP5-8.5 scenario. During the reference period (1985–2014), glaciers accounted for 85% of the streamflow, with smaller contributions from snowmelt and rainfall. By the mid-twenty-first century, a slight reduction in glacier melt contribution is anticipated, balanced by an increase in snowmelt. These changes are likely to have significant implications for downstream water availability, posing challenges for regional populations and water resource management
Creating and maintaining digital third places: orchestrating interaction ritual chains at a distance
Get PDFWith online and offline lives increasingly intertwined, hybrid retail spaces are emerging as new social hubs akin to classical third places. Third places refer to spaces apart from work and home, such as cafes and bars, that provide opportunities for social interaction. While prior research has primarily conceptualized third places as physical establishments, it also acknowledges that online environments, such as multiplayer gaming platforms or chatrooms, can fulfil similar functions. Yet, despite the recognized social-supportive role of retail venues, relatively little is known about how third place atmospheres can effectively be orchestrated in online retail settings. This study addresses this gap through an ethnographic investigation of a digital platform that recreates a physical third place online, enabling consumers to gather for long hours, consuming, conversing, and socializing. We find that, in online retail settings, third place atmospheres can be cultivated through the deliberate orchestration of technology-mediated interaction ritual chains. Through three interconnected processes – ritual framing, boundary regulation, and affective synchronization – that unfold before, during, and after the gatherings, the online setting transforms into a digital third place. Both retailers and consumers play pivotal roles in this transformation. Drawing on these findings, we offer several theoretical contributions and managerial recommendations
The emotional impact of nature seen through the lenses of virtual reality (VR) and revealed through the power of expressive art
Get PDFThis chapter explores the integration of Virtual Reality (VR) technology, expressive art, and nature exploration to enrich educational experiences and enhance education. The VR-ART project aimed to foster a deeper connection to nature by using VR to evoke emotions and visual art to facilitate the exploration and expression of those feelings. The project’s outcomes were transformed into pedagogical artifacts for Pre-Service Teachers (PSTs), offering practical examples and opportunities for reflective practice. These resources serve as exemplars of innovative teaching approaches, highlighting the potential of combining technology, art, and nature to create meaningful learning experiences and foster hope
A plasticity model for plate anchors under V-H combined loading in sand considering fabric anisotropy
No full textThis paper presents a series of numerical investigations into the failure envelope of plate anchors under V-H combined loading in sand using an advanced soil constitutive model that considers the evolution of fabric anisotropy. The influences of embedment ratio, relative density, and load inclination angle on the V-H failure envelope are discussed. Based on the numerical data, a plasticity model is proposed for efficiently reproducing the force–displacement behaviours of plate anchors under V-H combined loading. The proposed plasticity model employs a novel hardening law that includes an additional hardening parameter which is demonstrated to be necessary for considering combined loading. The effectiveness of the proposed plasticity model is demonstrated by retrospective simulations to the finite element simulations
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