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An explorative study on movement detection using wearable sensors in acute care hospital patients
Single-cell microRNA-mRNA co-sequencing techniques convey large potential for understanding microRNA regulations but require careful and systemic approaches
Boosting oxygen reduction performances in Pd-based metallenes by co-confining interstitial H and p-block single atoms
Ca2+-dependent cytoplasmic and nuclear phosphorylation of STOP1 by CPK21 and CPK23 confers ALMT1-dependent aluminum resistance
Reshaping the landscape of locoregional treatments for breast cancer liver metastases: A novel, intratumoral, p21-targeted percutaneous therapy increases survival in BALB/c mice inoculated with 4T1 triple negative breast cancer cells in the liver
Patients with disseminated metastatic disease from breast cancer are likely to have liver involvement in >50% of cases at some point during disease progression. These patients have a poor prognosis; and, when treated with the standard of care systemic therapy they have a median survival of <9-months. Increasing survival in breast cancer patients will likely require the administration of better therapies that are specifically targeted to treat distant metastases. One approach to increasing treatment efficacy for breast cancer liver metastases is through the application locoregional therapies. Locoregional therapies are an appealing interventional approach for breast cancer patients with liver metastases since these tumor lesions are accessible via minimally invasive procedures that can be administered using either ultrasound or CT imaging. Current locoregional therapies to treat breast cancer liver metastases are non-specific and have not produced significant increases in survival. The goal of this study was to design and test a targeted locoregional therapeutic intervention for breast cancer liver metastases. The lead candidate, a fixed-dose small-molecule drug called MBC-005, was tested in vitro and then the efficacy was evaluated in a BALB/c mouse liver metastases model. A novel formulation of N-allyl noroxymorphone hydrochloride incorporated into an alginate-based gel overcomes many of the limitations associated with the administration of small-molecule drugs, which include solubility, off-target toxicity, and enzymatic degradation. In vitro results demonstrated that MBC-005 mediated its anti-tumorigenic effect through a p21-dependent mechanism via a novel molecular pathway, in which N-allyl noroxymorphone component of MBC-005 stimulated the opioid growth factor receptor to increase p21 expression. Intratumoral administration of MBC-005 increased survival 3.9-fold in mice and significantly decreased tumor volume 4-fold. While many cytotoxic therapies increase p21 expression as a response to DNA damage, MBC-005 increased p21 expression independent cytotoxic DNA damage. MBC-005 did not induce off-target toxicity; and, as such, would be amenable to multiple rounds of administration. Nevertheless, it is notable that the positive effects of MBC-005 treatment on increasing survival and decreasing tumor volume in mice was achieved using a single dose.
Widespread freshwater non-native fishes exhibit synchronized population dynamics with functionally similar natives
β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1
Determination of radiocarbon in environmental objects
This article presents the results of radiocarbon distribution in natural components of ‘Degelen’ test location. It was used to conduct underground nuclear tests at the Semipalatinsk Test Site. Near-entry areas with water inflows were selected for research. Soil, plant and water samples were taken, in which the radiocarbon content was determined. The 14С activity concentration was determined using a highly sensitive alpha-beta radiometer SL-300 (ISO 13162, 2021). Sample preparation was carried out using a modern automated system Pyrolyser-6 Trio (Raddec International Ltd, UK). In the course of research undertaken, radiocarbon was revealed to be nonuniformly distributed in environmental objects. The effectiveness of Pyrolyser-6 Trio calcination and ashing system for 14C determination in environmental matrices has been demonstrated.
A method for spatial interpretation of weakly supervised deep learning models in computational pathology
Abstract Deep learning enables the modelling of high-resolution histopathology whole-slide images (WSI). Weakly supervised learning of tile-level data is typically applied for tasks where labels only exist on the patient or WSI level (e.g. patient outcomes or histological grading). In the weakly supervised learning context, there is a need for a methodology that facilitates the identification of the precise spatial regions in WSI that drive the prediction of the slide label. Such information is also needed for any further spatial interpretation of predictions from such models. We propose a novel method, Wsi rEgion sElection aPproach (WEEP), for model interpretation. It provides a principled yet straightforward way to establish the spatial area of WSI required for assigning a particular prediction label. We demonstrate WEEP on a binary classification task in the area of breast cancer computational pathology. WEEP facilitates the identification of spatial regions in WSI that are driving the decision making of a particular weakly supervised learning model, which can be further visualised and analysed to provide spatial interpretability of the model. The method is easy to implement, is directly connected to the model-based decision process, and offers information relevant to both research and diagnostic applications.
A phase I/II trial of WT1-specific TCR gene therapy for patients with acute myeloid leukemia and active disease post-allogeneic hematopoietic cell transplantation: skewing towards NK-like phenotype impairs T cell function and persistence
Abstract Relapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8+ T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (TTCR-C4) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4 in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, TTCR-C4 cells did not clearly improve outcomes despite EBV-specific TTCR-C4 cells showing enhanced potential for prolonged persistence compared to CMV-specific TTCR-C4. Investigating the fate of persisting TTCR-C4, we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting TTCR-C4 persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML.
Sex differences in pre-surgical respiratory physiotherapy impact on hospital and ICU stay in cardiac surgery patients: An observational study
Introduction Cardiovascular diseases may be amenable to surgical intervention. To mitigate post-surgical complications, diverse strategies are employed, including pre-habilitation programs. This study examines the effect of an unsupervised pre-surgical respiratory physiotherapy program on both sexes in terms of hospital and intensive care unit (ICU) stay lengths, as well as the incidence of post-surgical complications, their severity, and mortality risk. Methodology Retrospective observational study of 418 adults who underwent open-heart surgery between 2018 and 2022. The subjects were divided into two sex-based groups based on attendance at individual pre-surgical physiotherapy sessions. A Mann-Whitney U test was employed to evaluate the impact of the pre-surgical respiratory physiotherapy program and a Kruskal-Wallis rank-sum test to assess its influence on both sexes. Additionally, a multiple linear regression analysis was conducted to evaluate the impact of various variables on overall length of stay. Results The mean age of women was higher (p = 0.002), and they exhibited longer mean lengths of ICU (p = 0.004) and hospital stays (p = 0.031). In both sexes, a statistically significant reduction in LOS was observed among those undergoing a respiratory physiotherapy program. The linear regression analysis indicated that male sex was associated with a reduction in hospital and ICU stay lengths (p < 0.001). Although women experienced a higher number of complications (p = 0.043), no differences in severity levels or mortality risk were observed between sexes. Conclusion An unsupervised home pre-surgical physiotherapy program based on ventilatory exercises can reduce hospital and ICU stay for both men and women. Notwithstanding the higher incidence of complications in women, no differences in severity or mortality risk were observed between sexes.
Interpretable machine learning models for predicting childhood myopia from school-based screening data
Liquid-liquid phase separation-boosted transmembrane delivery in interactive protocell communities
Retraction: Evidence for a Pro-proliferative Feedback Loop in Prostate Cancer: The role of Epac1 and COX-2-dependent Pathways
Development of a prognostic model for chemotherapy response and identification of TNFAIP2 as a target in colorectal cancer
The origin of vertebrate teeth and evolution of sensory exoskeletons
Chiral substrate-induced chiral covalent organic framework membranes for enantioselective separation of macromolecular drug
Toxic behaviour facilitates echo chammber formation: An agent-based modelling simulation of science attitudes based on Spiral of Silence Theory
The Internet and social media have facilitated the spread of misinformation and the formation of echo chambers online. These echo chambers may facilitate the adoption of false beliefs and associated costs, but the mechanism of their formation remains a matter of debate. Based on Spiral of Silence Theory, sanctions against opposing views in the form of toxic online behaviour may enable not only the suppression of minority views but also the formation of echo chambers as those with suppressed minority views may attempt to find like-minded individuals who they can safely share their opinions with while avoiding toxic reprisals from those with an opposing view. In the current paper, we introduce the Pro- and Anti-Science Opinions Model (PASOM)—an agent-based model where agents decide between a pro- or anti-science view on a single science-based topic. PASOM uniquely allows agents to choose whether to interact toxically or persuasively. Initial simulations showed that toxic behaviour in the model could push agents into echo chambers and drive agents to adopt strong pro- or anti-science views with most agents in all simulations finishing in an echo chamber. Subsequent simulations demonstrated the importance of toxic behaviour in the outcomes by reducing propensity to behave toxically and sensitivity to toxic behaviour, which resulted in concurrent reductions in echo chamber formation. Finally, simulation outcomes were compared to previously reported social media data and were able to successful reproduce outcomes observed in the empirical data. The various results suggest that toxic behaviour and people’s responses to it may be important factors in the formation of echo chambers and differences between social media platforms and topics.
Cryoelectrospun elastin-alginate scaffolds as potential cell delivery vehicles for mesenchymal stromal cell therapy
Abstract Salivary gland fibrosis results in salivary hypofunction whose current treatments are palliative. Mesenchymal stem/stromal cells (MSCs) are anti-fibrotic and anti-inflammatory and provide a promising alternative to treat fibrosis, but face translational challenges due to poor tissue targeting and retention. Scaffolds could facilitate targeted MSC delivery and improve MSC retention. Here, we demonstrated the feasibility of using stromal extracellular matrix (ECM)-mimicking elastin-alginate cryoelectrospun scaffolds (CES) for MSC delivery. Using MSC-like primary embryonic salivary mesenchyme cells (SMSCs), we demonstrated that CES supported viable, healthy and non-fibrotic long-term stromal cell maintenance while suppressing the fibrotic phenotype in myofibroblasts. We established an in vitro fibrosis model by coculturing SMSCs and myofibroblasts on CES and validated that SMSCs on CES imparted anti-fibrotic effects on myofibroblasts; however, these effects were suppressed by TGF-β1. In vivo orthotopic implantation of CES and SMSC-CES constructs showed that CES were biocompatible, non-inflammatory, and non-fibrotic, however, they did not remediate fibrosis. Further, supplementation of anti-fibrotic FGF2 to the in vitro fibrosis model demonstrated partial rescue of the anti-fibrotic effects of SMSC-CES constructs on myofibroblasts stimulated by TGF-β1 signaling. These studies set the premise for multi-pronged therapeutic approaches and validate CES as a potential stromal cell delivery vehicle in regenerative medicine applications.