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UNLABELLED: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for "response" and ultimately lead to identification of effective treatments.

Alternative lengthening of telomeres (ALT) is a homologous recombination-based telomere maintenance mechanism. It is active in approximately 10-15% of cancers. We present a DNA-fiber protocol, combining YOYO-1 staining of genomic DNA, telomere fluorescence in situ hybridization (FISH), and EdU labeling of nascent DNA, to measure telomere extension events in ALT cancer cells. The protocol can be used to delineate ALT-mediated telomere extension. For complete details on the use and execution of this protocol, please refer to Barroso-Gonzalez et al. (2021).

BackgroundGlioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care is surgery followed by radiotherapy and temozolomide, leading to a median survival time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating cells (GICs), responsible for therapy resistance and tumor recurrence, suggesting that targeting GICs could improve treatment response. ONC201 is a first-in-class anti-tumor agent with clinical efficacy in some forms of high-grade gliomas. Here we test its efficacy against GBM in combination with radiation.MethodsUsing patient-derived GBM lines and mouse models of GBM we test the effects of radiation and ONC201 on GBM self-renewalin vitro and survivalin vivo.A possible resistance mechanism is investigated using RNA-Sequencing.ResultsTreatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viabilityin vitro. ONC201 exhibited anti-tumor effects on radioresistant GBM cells indicated by reduced self-renewal in secondary and tertiary glioma spheres. Combined treatment of ONC201 and radiation prolonged survival in syngeneic and patient-derived orthotopic xenograft mouse models of GBM. Subsequent transcriptome analyses after combined treatment revealed shifts in gene expression signatures related to quiescent GBM populations, GBM plasticity, and GBM stem cells.ConclusionsOur findings suggest that combined treatment with the DRD2/3 antagonist ONC201 and radiation improves the efficacy of radiation against GBMin vitroandin vivothrough suppression of GICs without increasing toxicity in mouse models of GBM. A clinical assessment of this novel combination therapy against GBM is further warranted.

In tertiary education, generic professional skills should be developed along with discipline-specific knowledge and skills. Team-Based Learning (TBL), an active learning strategy, creates deep learning and enhanced student engagement; however, its effects on the development of generic learning outcomes are unknown. The aim of this study was to evaluate postgraduate specialty nursing students' perspectives of how TBL impacts the acquisition of skills defined by the university's eight Graduate Learning Outcomes (GLOs). A descriptive exploratory design was used in this study. Postgraduate nursing students in 2016-2017 at one university were invited to participate. Data were collected via demographic survey, a ranking tool, and written reflections. Data were analysed using descriptive statistics and content analysis. The response rate was 97.2 per cent (172/177). Participants were mostly females (n=152, 88.4%) aged 25-34 years (n=115, 66.9%). Student (n=156) rankings showed TBL contributed to the acquisition of critical thinking (n=90, 57.7%) and problem solving skills (n=56, 35.9%) the most. Students (n=144) made 2719 comments regarding how TBL led to the acquisition of GLOs in written reflections. Almost 98 per cent (n=2657) of all reflective comments were positive. All students mentioned at least one GLO positively due to TBL. Most positive reflections related to self-management (n=520, 19.6%) and communication (n=434, 16.3%). Postgraduate specialty nursing students perceived TBL classes contributed to the acquisition of their university's GLOs, particularly critical thinking, problem solving, and self-management skills. The active learning strategy of TBL facilitates learning and engagement, and the attainment of essential professional attributes which are highly valued by employers.

AbstractAcademic procrastination is one of the main problems students encounter during studying. It affects their mental health, academic performance, and even everyday activities. A lack of time management was once thought to be the cause of procrastination. Procrastination, however, has been linked to mood control, according to recent studies. Decision-making is also a factor that is influenced by emotion or a person’s affect. The present study aims to find whether decision-making and affective styles influence academic procrastination among Indian students. The participants (N = 211) who are currently studying any discipline in a regular mode and who are between the ages of 17 to 30 years (mean = 21.10 & SD = 2.168) were selected using purposive sampling, and data was collected online using Academic Procrastination Scale, General Decision-Making Style Instrument and Affective Style Questionnaire. Data were analyzed using Pearson correlation, along with multiple regression analysis. Results found a significant inverse correlation between rational decision-making and academic procrastination and a weak inverse correlation between adjusting affective style and academic procrastination. A significant positive correlation between avoidant decision-making and academic procrastination was also found. Through regression analysis avoidance, decision-making has been found as a positive predictor of academic procrastination along with rational decision-making, and spontaneous decision-making as negative predictors. No significant correlations were found for academic procrastination with intuitive, dependent, spontaneous, concealing, and tolerating styles. The current results contribute to the existing literature on academic procrastination and the development of effective strategies to reduce academic procrastination by managing unhealthy decision-making styles.

AbstractBoth hedonia and eudaimonia contribute to well-being, but existing literature on alcohol-dependence concentrates on hedonic needs alone, leaving a research gap on the role of eudaimonia in alcohol-dependence. Theoretically, mindfulness promotes eudaimonia that presumably benefits individuals with alcohol-dependence, but the empirical literature on the same is scarce. Hence, the current pilot study intended to examine the association of eudaimonia and mindfulness with alcohol-dependence, and assess the feasibility of the main study. Study-I compared mindfulness and eudaimonia of individuals with (N = 154) and without (N = 160) alcohol-dependence. Its results called forth a study-II that explored the role of eudaimonia and mindfulness in predicting alcohol-dependence among the individuals undergoing treatment for alcohol-dependence (N = 110). The data were analyzed using the independent-sample t-test, Pearson correlation, and multiple linear regression. Study-I revealed the significant deficiency of mindfulness and eudaimonia among individuals with alcohol-dependence compared to those without alcohol-dependence. Study-II found that mindfulness and eudaimonia predicted alcohol-dependence and alcohol craving. Study result indicates the potential role of mindfulness and eudaimonia in the effective treatment of alcohol-dependence, through significant correlation among the variables. The study also highlights the feasibility and utility of the main study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BACKGROUND: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS: Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION: The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

The collapse of stalled replication forks is a major driver of genomic instability. Several committed mechanisms exist to resolve replication stress. These pathways are particularly pertinent at telomeres. Cancer cells that use Alternative Lengthening of Telomeres (ALT) display heightened levels of telomere-specific replication stress, and co-opt stalled replication forks as substrates for break-induced telomere synthesis. FANCM is a DNA translocase that can form independent functional interactions with the BLM-TOP3A-RMI (BTR) complex and the Fanconi anemia (FA) core complex. Here, we demonstrate that FANCM depletion provokes ALT activity, evident by increased break-induced telomere synthesis, and the induction of ALT biomarkers. FANCM-mediated attenuation of ALT requires its inherent DNA translocase activity and interaction with the BTR complex, but does not require the FA core complex, indicative of FANCM functioning to restrain excessive ALT activity by ameliorating replication stress at telomeres. Synthetic inhibition of FANCM-BTR complex formation is selectively toxic to ALT cancer cells.

Objective Chronic low back pain (CLBP) is a prominent medical condition that can affect an individual at some point in their life time which could lead to poor quality of life (QOL). Low back pain has affected approximately 577 million individuals globally by 2017. The aim of the current systematic review is to synthesise the existing evidence on the factors influencing the QOL in individuals with CLBP and to identify strategies to improve their QOL. Method PubMed, ScienceDirect, PsychNet and Google Scholar were used to extract studies reporting quantitative relationships between QOL and its possible determinants in individuals having CLBP and the intervention strategies to improve QOL. Results 10,851 studies were initially identified and twenty-six studies which met the inclusion criteria were selected for the review. 21 studies reported relationship between QOL and potential determinants and five studies assessed the influence of interventions on QOL. Determinants were classified as kinesiophobia, fear avoidance belief, or pain belief; occupation-related factors; pain and disability; activity; personal factors including age, gender, employment status; and other psychological factors including anxiety, quality of sleep, and health locus of control. Intervention strategies including MBSR, Pilates method and Back School Programme improved QOL in individuals with CLBP. Conclusion Psychosocial factors as well as the physical status of the individual contributed to the QOL in individuals having CLBP.

Introduction: Healthcare-associated infections are a significant risk to patients and the healthcare system. Differences in knowledge, attitudes, and practices among nurses have limited standardized precautions. Improving self-efficacy can enhance compliance with standard precautions, protect patients, and preserve the credibility of healthcare institutions. Aim: This study aimed to determine the mediating effects of self-efficacy on nurses' knowledge, attitude, and compliance with standard precautions in Saudi Arabia. Methods: This cross-sectional study was conducted in four hospitals in Dharan, Saudi Arabia, between July and October 2023. The respondents were selected through a multistage sampling of 305 nurses from wards and special areas. Results: participants demonstrated a moderate level of knowledge (M = 19.00, SD = 2.17), positive attitudes (M = 55.86, SD = 10.22), intermediate compliance (M = 72.44, SD = 11.47), and moderate self-efficacy (M = 29.99, SD = 11.40). Respondents who possessed more knowledge demonstrated positive attitudes toward standard precautions (r = 0.256, p < 0.001) and were more likely to comply (r = 0.376, p < 0.001). Higher self-efficacy levels were significantly positively correlated with knowledge (r = 0.391, p < 0.001), attitude (r = 0.311, p < 0.001), and compliance (r = 0.385, p < 0.001). The direct effect of knowledge on compliance was estimated to be 0.115 (p < 0.001), while the direct effect of attitude was slightly weaker (0.014, p = 0.049). Self-efficacy indirectly increased compliance through its influence on knowledge and attitude, with indirect effects of 0.039 (p < 0.001) and 0.008 (p = 0.002), respectively. Conclusions: Nurses with higher knowledge of infection control and positive attitudes toward established protocols were more likely to comply consistently. This association is further strengthened by self-efficacy. This confidence enhanced their understanding of the specific procedures, reinforced their positive beliefs about the importance of protocols, and ultimately led to greater adherence. [ABSTRACT FROM AUTHOR]

Background: Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells. Methods: Flow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer. Results: ONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model. Conclusions: ONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo. [ABSTRACT FROM AUTHOR]

Abstract As per the reports of WHO, the COVID-19, first reported in December 2019, put the whole world in an unprecedented crisis and lingering uncertainty with innumerable deaths, generalised economic depression, unemployment, quarantine, unavoidable lockdown, and travel-ban that was imposed globally as a necessity to tackle the pandemic. Among the populace, the migrants were found to be one of the most vulnerable groups in this lockdown, as their very livelihood came to a complete standstill. This review-paper aims to investigate in detail the multiple facets of adversities the migrants went through in India during the lockdown and the socio-psychological impact of circular migration. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, studies on migrant workers during COVID-19 and on circular migration were searched. Database searches on Scopus, PubMed, and PsychNet and manual searches on Google Scholar were carried out. From the initially identified 15,697 articles, 15 articles that met the inclusion criteria were chosen for review. The findings highlight the different plight of the migrants, who had the pressing need to head back home to safety despite the acute financial crisis and the travel problems. The poor quality of the relief camps with meagre rations and lack of facilities especially put the women and children in distress and generated a lot of psychosocial issues. The present study urges the mental health-care professionals to groom themselves for facing the challenges of a surge in mental illnesses by taking necessary measures. It also emphasises the need to establish a strong ethical alliance between the local population, health systems, local government mechanisms, and human rights associations in order to take a relook at the national migration policies.

The intensity and frequency of rapes and attempted sexual assaults on women, along with several unreported cases, are rising alarmingly in countries including India. National Crime Records Bureau in 2018 reported one rape every 15 min in India. Additionally, according to the NCRB data, up to 91 rapes were reported in the country on a single day. This scenario, therefore, calls for the immediate attention of the researchers to explore the factors that contribute to such crimes. The current qualitative study, hence, was intended to explore the socio-cultural and psychological factors associated with rape from the perspectives of men. The current study was conducted among 37 males between the ages of 18 and 25 years. The data were collected using semi-structured interviews. The thematic analysis threw light on the development of several main themes and sub-themes for socio-cultural and psychological factors associated with rape. The important main themes that emerged include attitude towards rape, sexual restriction, masculine dominance, westernization, lack of social support, exploitation, perception and attitude toward law, psychological impact, and childhood trauma. The study had identified several socio-cultural factors that possibly contribute to sexual aggression against women; the psychological consequences of rape on the victims; and the role of societal norms that indirectly result in increased incidents of sexual assaults. The results would facilitate recognition, development, and implementation of social interventions to control the prevalence of rape in the country.