Cmpd10357 to treat B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of cancer found in children. Although the overall survival rates are now >80%, 15%-20% of pediatric patients relapse, with survival rates subsequently dropping to 5%-10%. Cmpd10357, 3-amino-5-arylamino-6-chloro-N- (diaminomethylene) pyrazine-2-carboximide, is a highly potent, cell-permeant compound recently shown to have cytotoxic effects on solid tumors, including human breast cancer and high-grade gliomas, independent of their proliferative status. Cmpd10357 demonstrated concentration-dependent cytotoxicity in two human B-ALL cell lines, JM1 and Reh, at half-maximal inhibitory concentrations (IC50) of 3.2 and 3.3 µM, respectively. Cmpd10357, at a dose of 5 mg/kg, significantly prolonged survival in our B-ALL xenograft mouse model, with a median survival time of 49.0 days compared with 45.5 days in the control group (p < 0.05). The cytotoxicity of Cmpd10357 demonstrated caspase-independent, nonapoptotic cancer cell demise associated with the nuclear translocation of apoptosis-inducing factor (AIF). The cytotoxicity of Cmpd10357 in B-ALL cells was inhibited by Necrostatin-1 but not by Necrosulfonamide. These studies suggest that an AIF-mediated, caspase-independent necrosis mechanism of Cmpd10357 in B-ALL could be used in combination with traditional apoptotic chemotherapeutic agents.

Human Induced Pluripotent Stem Cell Encapsulation Geometry Impacts Three-Dimensional Developing Human Engineered Cardiac Tissue Functionality.

Cardiac tissue engineering has been working to alleviate the immense burden of cardiovascular disease for several decades. To improve cardiac tissue homogeneity and cardiomyocyte (CM) maturation, in this study, we investigated altering initial encapsulation geometry in a three-dimensional (3D) direct cardiac differentiation platform. Traditional engineered cardiac tissue production utilizes predifferentiated CMs to produce 3D cardiac tissue and often involves various cell selection and exogenous stimulation methods to promote CM maturation. Starting tissue formation directly with human induced pluripotent stem cells (hiPSCs), rather than predifferentiated CMs, simplifies the engineered cardiac tissue formation process, making it more applicable for widespread implementation and scale-up. In this study, hiPSCs were encapsulated in poly (ethylene glycol)-fibrinogen in three tissue geometries (disc-shaped microislands, squares, and rectangles) and subjected to established cardiac differentiation protocols. Resulting 3D engineered cardiac tissues (3D-ECTs) from each geometry displayed similar CM populations (∼65%) and gene expression over time. Notably, rectangular tissues displayed less tissue heterogeneity and suggested more advanced features of maturing CMs, including myofibrillar alignment and Z-line formation. In addition, rectangular tissue showed significantly higher anisotropic contractile properties compared to square and microisland tissues (MI 0.28 ± 0.03, SQ 0.35 ± 0.05, RT 0.79 ± 0.04). This study demonstrates a straightforward method for simplifying and improving 3D-ECT production without the use of exogenous mechanical or electrical pacing and has the potential to be utilized in bioprinting and drug testing applications. Impact statement Current methods for improving cardiac maturation postdifferentiation remain tedious and complex. In this study, we examined the impact of initial encapsulation geometry on improvement of three-dimensional engineered cardiac tissue (3D-ECT) production and postdifferentiation maturation for three tissue geometries, including disc-shaped microislands, squares, and rectangles. Notably, rectangular 3D-ECTs displayed less tissue heterogeneity and more advanced features of maturing cardiomyocytes, including myofibrillar alignment, Z-line formation, and anisotropic contractile properties, compared to microisland and square tissues. This study demonstrates an initial human induced pluripotent stem cell-encapsulated rectangular tissue geometry can improve cardiac maturation, rather than implementing cell selection or tedious postdifferentiation manipulation, including exogenous mechanical and/or electrical pacing.

Cyanidin improves oocyte maturation and the in vitro production of pig embryos.

The objective of this study was to reduce the negative effects of oxidative stress by decreasing the levels of reactive oxygen species (ROS) through supplementation of the major antioxidants present in elderberries: kuromanin and cyanidin. Oocytes (n = 1150) were supplemented with 100 or 200 µM of kuromanin or cyanidin during maturation, and then evaluated for ROS levels or fertilized and evaluated for penetration, polyspermic penetration, male pronucleus formation, and embryonic development. The ROS levels and incidence of polyspermic penetration were lower (P < 0.05) in oocytes supplemented with 100 µM cyanidin when compared with other treatments. Supplementation of 100 µM cyanidin increased (P < 0.05) MPN and blastocyst formation compared with other treatments. However, supplementation of 100 µM kuromanin did not have significant effects on the criteria evaluated, and supplementation of 200 µM kuromanin had significant (P < 0.05) detrimental effects for each criterion. Additional oocytes (n = 1438) were supplemented with 100 µM cyanidin during maturation and evaluated for glutathione, glutathione peroxidase, catalase, and superoxide dismutase activity. Supplementation of 100 µM cyanidin increased (P < 0.05) catalase activity and intracellular GSH levels compared with no supplementation of cyanidin. These results indicate that supplementing cyanidin during maturation reduces oxidative stress by reducing ROS levels and increasing GSH concentrations within the oocyte.

Toric Spines at a Site of Learning.

We discovered a new type of dendritic spine. It is found on space-specific neurons in the barn owl inferior colliculus, a site of experience-dependent plasticity. Connectomic analysis revealed dendritic protrusions of unusual morphology including topological holes, hence termed "toric" spines (n = 76). More significantly, presynaptic terminals converging onto individual toric spines displayed numerous active zones (up to 49) derived from multiple axons (up to 11) with incoming trajectories distributed widely throughout 3D space. This arrangement is suited to integrate input sources. Dense reconstruction of two toric spines revealed that they were unconnected with the majority (∼84%) of intertwined axons, implying a high capacity for information storage. We developed an ex vivo slice preparation and provide the first published data on space-specific neuron intrinsic properties, including cellular subtypes with and without toric-like spines. We propose that toric spines are a cellular locus of sensory integration and behavioral learning.

Becoming an occupational therapist: perceived influence of international fieldwork placements on clinical practice.

BACKGROUND: Many occupational therapy programs have augmented curricula to provide students with opportunities to engage in international fieldwork placements (IFPs). However, limited research exists exploring the perceived influence that IFPs may have on future occupational therapy roles and characteristics. PURPOSE: The purpose of this study is to explore how Canadian occupational therapists who participated in IFPs as students perceive the influence of their IFP experience on their subsequent practice. METHOD: Semistructured interviews were conducted with 20 occupational therapists who participated in IFPs as occupational therapy students. The interview guide was developed based on the Profile of Occupational Therapy Practice in Canada and relevant literature. A directed content analysis was used in conjunction with the DEPICT model of data analysis to guide the analysis process and summarize the results. FINDINGS: Participants described how IFPs nurtured the development of six skills, or active ingredients, which supported the development of competence in occupational therapy roles. IFPs were also perceived as providing a competitive edge. IMPLICATIONS: This study suggests that IFPs shape the development of competence in key practice skills and occupational therapy roles.

Cardiorespiratory and metabolic responses associated with children's physical activity during self-paced games.

The aim of this study was to explore the possibility of identifying clusters of children's games based on estimated energy expenditures and (or) intensity when performed in a guided active play format. The study also investigated whether the identified active play game clusters were repeatable when the games were performed on different days. Children (9.7 ± 1.1 years; n = 12) were assessed for oxygen consumption, heart rate, energy expenditure (EE), and metabolic equivalent (MET) on a treadmill (at 4, 6, and 8 km·h(-1) (0% grade)). HR and ActiGraph GT1M accelerometer (ACC) generated linear regression equations were used to estimate EE. The ACC (3 s epochs) were used for estimating METs in assigning percent time at medium-vigorous physical activity (%MVPA) of 10 self-paced games. The results showed a consistent range of EEs (ACC-equation) from 13.57 kcal·(5 min)(-1) to 25.00 kcal·(5 min)(-1) (p < 0.05); EEs (HR-equation) from 29.72 to 42.49 kcal·(5 min)(-1) (p < 0.05); and %MVPA from 10% to 34% (p < 0.05) (from ACC equations) across all games. These were reproducible from day to day (p > 0.05). This study confirms the existence of active play children's game clusters that might be useful in formatting guided active play in a dose-response manner for children.

Fatigue management by speech-language pathologists for adults with traumatic brain injury.

This study uses a qualitative approach to examine common techniques used by speech-language pathologists (SLPs) to manage fatigue in communication intervention following traumatic brain injury (TBI). Thirteen SLPs from New Zealand hospital and rehabilitation services completed semi-structured interviews in which they discussed their current management strategies. A number of management-related themes recurred throughout the interviews, highlighting the basis of fatigue-management-focused (FMF) communication intervention. The four fatigue-related themes were: intervention structure, client and family strategies, monitoring by both the client and therapist, and lifestyle and daily activities. From these four themes, a model of current SLP practice was developed for clients with TBI. This model will provide the basis for future studies evaluating the effectiveness of FMF communication intervention.