Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment.

Pancreatic cancer remains a formidable challenge due to limited treatment options and its aggressive nature. In recent years, the naturally occurring anticancer compound juglone has emerged as a potential therapeutic candidate, showing promising results in inhibiting tumor growth and inducing cancer cell apoptosis. However, concerns over its toxicity have hampered juglone's clinical application. To address this issue, we have explored the use of polymeric micelles as a delivery system for juglone in pancreatic cancer treatment. These micelles, formulated using Poloxamer 407 and D-α-Tocopherol polyethylene glycol 1000 succinate, offer an innovative solution to enhance juglone's therapeutic potential while minimizing toxicity. In-vitro studies have demonstrated that micelle-formulated juglone (JM) effectively decreases proliferation and migration and increases apoptosis in pancreatic cancer cell lines. Importantly, in-vivo, JM exhibited no toxicity, allowing for increased dosing frequency compared to free drug administration. In mice, JM significantly reduced tumor growth in subcutaneous xenograft and orthotopic pancreatic cancer models. Beyond its direct antitumor effects, JM treatment also influenced the tumor microenvironment. In immunocompetent mice, JM increased immune cell infiltration and decreased stromal deposition and activation markers, suggesting an immunomodulatory role. To understand JM's mechanism of action, we conducted RNA sequencing and subsequent differential expression analysis on tumors that were treated with JM. The administration of JM treatment reduced the expression levels of the oncogenic protein MYC, thereby emphasizing its potential as a focused, therapeutic intervention. In conclusion, the polymeric micelles-mediated delivery of juglone holds excellent promise in pancreatic cancer therapy. This approach offers improved drug delivery, reduced toxicity, and enhanced therapeutic efficacy.

The relationships between pain-associated psychological distress, pain intensity, patient expectations, and physical function in individuals with musculoskeletal pain: A retrospective cohort study.

INTRODUCTION: The presence of pain-associated psychological distress (PAPD) in musculoskeletal disorders, including negative mood, fear-avoidance, and lack of positive affect/coping, is associated with prolonged disability. The importance of considering psychological influence on pain is well known, but practical ways of addressing it are not as straightforward. Identifying relationships between PAPD and pain intensity, patient expectations, and physical function may guide the development of future studies that assess causality and inform clinical practice. OBJECTIVE: To assess the relationship between PAPD measured by the Optimal Screening for Prediction of Referral and Outcome-Yellow Flag tool, and baseline pain intensity, expectations of treatment effectiveness, and self-reported physical function at discharge. DESIGN: Retrospective cohort study. SETTING: Hospital-based outpatient physical therapy. PARTICIPANTS: Patients 18 to 90 years old with spinal pain or lower extremity osteoarthritis. MAIN OUTCOME MEASURES: Pain intensity and patient expectations of treatment effectiveness at intake, and self-reported physical function at discharge. RESULTS: A total of 534 patients, 56.2% female, median (interquartile range [IQR]) age 61 (21) years with an episode of care between November 2019 and January 2021 were included. A multiple linear regression showed a significant association between PAPD and pain intensity with 6.4% (p < .001) of the variance explained. PAPD explained 3.3% (p < .001) of the variance in patient expectations. One additional yellow flag present resulted in a 0.17-point increase in pain intensity and 1.3% decrease in patient expectations. PAPD was also associated with physical function with 3.2% (p < .001) of the variance explained. PAPD explained 9.1% (p < .001) of the variance in physical function at discharge in the low back pain cohort only when assessed independently by body region. CONCLUSION: These findings support the theory that the pain experience is complex and multiple factors should be considered when evaluating a patient with musculoskeletal pain. Clinicians who have identified PAPD may consider these relationships when planning or modifying interventions and pursuing multidisciplinary collaboration.

Predictors of clinical experience performance in occupational therapy and physiotherapy: A scoping review.

INTRODUCTION: Successful completion of clinical education experiences is a graduation requirement for students in occupational therapy and physical therapy programmes. A scoping review was conducted to determine what is known about possible clinical experience performance predictors and to find associated research gaps. METHODS: The search included one hand-searched journal and seven databases, which were used to identify related relevant studies: CINAHL, Education Database, Education Source, Education Resources Information Center (ERIC), PubMed, REHABDATA, and Web of Science. A research librarian guided the search process, and the review's reporting is structured by the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. Studies were included if they contained predictors of clinical experience success indicated by validated performance evaluation tools that were scored by clinical instructors. A multidisciplinary team reviewed the title, abstract, and full text for inclusion and conducted thematic data synthesis to categorise findings. FINDINGS: Twenty-six articles met the inclusion criteria. The majority of articles were of correlational design and included single institutions. Seventeen articles included occupational therapy, eight included physical therapy, with only one article including both programmes. Four categories of predictors of clinical experience success were identified: pre-admission variables, academic preparation, learner characteristics, and demographics. Each of the main categories included three to six subcategories. Key findings included the following: (a) The most common cited predictors in clinical experiences are academic preparation and learner characteristics, (b) more experimental design studies are needed to determine the causal relationship between predictors and clinical experience success, and (c) future research is needed on ethnic disparities and clinical experience success. CONCLUSION: Findings from this review show that possible predictors of clinical experience success include a wide range of factors when correlating success with a standardised tool. Academic preparation and learner characteristics were the most investigated predictors. There were only a small number of studies that found a correlation with pre-admission variables. The findings of this study suggest that students' academic achievement may be a critical element of clinical experience preparation. Future research using experimental designs and across institutions is needed to determine the main predictors for student success.

BET inhibitors rescue anti-PD1 resistance by enhancing TCF7 accessibility in leukemia-derived terminally exhausted CD8+ T cells.

Many acute myeloid leukemia (AML) patients exhibit hallmarks of immune exhaustion, such as increased myeloid-derived suppressor cells, suppressive regulatory T cells and dysfunctional T cells. Similarly, we have identified the same immune-related features, including exhausted CD8+ T cells (TEx) in a mouse model of AML. Here we show that inhibitors that target bromodomain and extra-terminal domain (BET) proteins affect tumor-intrinsic factors but also rescue T cell exhaustion and ICB resistance. Ex vivo treatment of cells from AML mice and AML patients with BET inhibitors (BETi) reversed CD8+ T cell exhaustion by restoring proliferative capacity and expansion of the more functional precursor-exhausted T cells. This reversal was enhanced by combined BETi and anti-PD1 treatment. BETi synergized with anti-PD1 in vivo, resulting in the reduction of circulating leukemia cells, enrichment of CD8+ T cells in the bone marrow, and increase in expression of Tcf7, Slamf6, and Cxcr5 in CD8+ T cells. Finally, we profiled the epigenomes of in vivo JQ1-treated AML-derived CD8+ T cells by single-cell ATAC-seq and found that JQ1 increases Tcf7 accessibility specifically in Tex cells, suggesting that BETi likely acts mechanistically by relieving repression of progenitor programs in Tex CD8+ T cells and maintaining a pool of anti-PD1 responsive CD8+ T cells.

Reproducibility of resistance exercise therapy interventions in trials for chronic low back pain is challenging: A systematic review.

OBJECTIVE: Determine reproducibility of resistance exercise regimens in trials for CLBP and determine if recently available checklists are effective. METHODS: Four databases (Medline, PubMed, Cochrane and CINAHL) were searched for keywords related to back pain and resistance exercise. Reproducibility was assessed using two checklists, the 12-item Template for Intervention Description and Replication (TIDieR) and the 19-item Consensus on Exercise Reporting Template (CERT). The proportion reporting was analysed, with additional comparison of trials pre- and post-availability of each checklist. A generalised linear regression was conducted with checklist items as the dependent variable and year of publication as the independent (PROSPERO ID = #CRD42020186036). RESULTS: Overall, details that facilitate reproducibility were under-reported. No trials reported all checklist items, while only 18 trials (35.5%) and 5 trials (9.8%) reported 75%+ of checklist items for the TIDieR and CERT, respectively. A median of 8 (IQR 2) of 12 TIDieR criteria were reported and a median of 9 (IQR 7) of 19 criteria were reported for the CERT. There was no difference pre/post checklist publication (TIDieR median before = 8 (IQR 2), after = 8 (IQR 2.25); CERT mean before = 9 (IQR 5.25), after = 9 (IQR 7)). Regression failed to support improved reporting over time. The majority of studies (86.3%) were scored as having an elevated risk of bias. CONCLUSIONS: Reproducibility of resistance exercise in CLBP trials appears questionable due to low levels of reporting. The publication reporting checklists have not resulted in improvement. Real-world reproducibility is questionable. There is a need to improve reporting to maximise reproducibility. IMPACT STATEMENT: The present results reveal a demand in improved reporting to ensure both enhanced clinical translation in the real-world and replicability to enhance knowledge of best-practice for resistance exercise in the CLBP population.

Transcriptome visualization and data availability at the Saccharomyces Genome Database.

The Saccharomyces Genome Database (SGD; www.yeastgenome.org) maintains the official annotation of all genes in the Saccharomyces cerevisiae reference genome and aims to elucidate the function of these genes and their products by integrating manually curated experimental data. Technological advances have allowed researchers to profile RNA expression and identify transcripts at high resolution. These data can be configured in web-based genome browser applications for display to the general public. Accordingly, SGD has incorporated published transcript isoform data in our instance of JBrowse, a genome visualization platform. This resource will help clarify S. cerevisiae biological processes by furthering studies of transcriptional regulation, untranslated regions, genome engineering, and expression quantification in S. cerevisiae.

Perceptions of the professional and personal impact of hybrid fellowship training: a qualitative study.

OBJECTIVES: This study aimed to elucidate graduate perceptions of how fellowship training impacted their post-training professional and personal lives. METHODS: Interviews were conducted with 13 graduates of a hybrid (e.g. blended-learning) fellowship program. All participants were at least 1 year post completion of fellowship to limit recall bias and allow for post-training personal and professional development. Qualitative analysis was performed on interview transcriptions using directed content analysis with two coders other than the interviewers, followed by discussion until agreement was reached if there were disputes related to coding analysis. If needed, arbitration was provided from one of two interviewers. RESULTS: Analysis revealed three primary constructs of post-fellowship impact: practical, social, and personal. Practical subthemes were centric to care delivery. Social subthemes extended to intra, inter, and non-professional connections. Personal subthemes noted professional and cognitive evolution. DISCUSSION: Participants clearly described impact extending well beyond day-to-day practice suggesting that fellowship impacted the whole person versus sole practitioner. This study may impact program structure and content inclusion for fellowship programs as well as providing support for fellows in training.

Saccharomyces genome database informs human biology.

The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is an expertly curated database of literature-derived functional information for the model organism budding yeast, Saccharomyces cerevisiae. SGD constantly strives to synergize new types of experimental data and bioinformatics predictions with existing data, and to organize them into a comprehensive and up-to-date information resource. The primary mission of SGD is to facilitate research into the biology of yeast and to provide this wealth of information to advance, in many ways, research on other organisms, even those as evolutionarily distant as humans. To build such a bridge between biological kingdoms, SGD is curating data regarding yeast-human complementation, in which a human gene can successfully replace the function of a yeast gene, and/or vice versa. These data are manually curated from published literature, made available for download, and incorporated into a variety of analysis tools provided by SGD.

Outreach and online training services at the Saccharomyces Genome Database.

The Saccharomyces Genome Database (SGD; www.yeastgenome.org ), the primary genetics and genomics resource for the budding yeast S. cerevisiae , provides free public access to expertly curated information about the yeast genome and its gene products. As the central hub for the yeast research community, SGD engages in a variety of social outreach efforts to inform our users about new developments, promote collaboration, increase public awareness of the importance of yeast to biomedical research, and facilitate scientific discovery. Here we describe these various outreach methods, from networking at scientific conferences to the use of online media such as blog posts and webinars, and include our perspectives on the benefits provided by outreach activities for model organism databases. Database URL: http://www.yeastgenome.org.

Using Portable Video Modeling Technology to Increase the Compliment Behaviors of Children with Autism During Athletic Group Play.

A multiple baseline design across participants was used to examine the effects of a portable video modeling intervention delivered in the natural environment on the verbal compliments and compliment gestures demonstrated by five children with autism. Participants were observed playing kickball with peers and adults. In baseline, participants demonstrated few compliment behaviors. During intervention, an iPad(®) was used to implement the video modeling treatment during the course of the athletic game. Viewing the video rapidly increased the verbal compliments participants gave to peers. Participants also demonstrated more response variation after watching the videos. Some generalization to an untrained activity occurred and compliment gestures also occurred. Results are discussed in terms of contributions to the literature.