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Glioblastoma multiforme (GBM) contains a subpopulation of cells, GBM stem cells (GSCs), that maintain the bulk tumor and represent a key therapeutic target. Norrin is a Wnt ligand that binds Frizzled class receptor 4 (FZD4) to activate canonical Wnt signaling. Although Norrin, encoded by NDP, has a well-described role in vascular development, its function in human tumorigenesis is largely unexplored. Here, we show that NDP expression is enriched in neurological cancers, including GBM, and its levels positively correlated with survival in a GBM subtype defined by low expression of ASCL1, a proneural factor. We investigated the function of Norrin and FZD4 in GSCs and found that it mediated opposing tumor-suppressive and -promoting effects on [ASCL1.sup.lo] and [ASCL1.sup.hi] GSCs. Consistent with a potential tumor-suppressive effect of Norrin suggested by the tumor outcome data, we found that Norrin signaling through FZD4 inhibited growth in [ASCL1.sup.lo] GSCs. In contrast, in [ASCL1.sup.hi] GSCs Norrin promoted Notch signaling, independently of WNT, to promote tumor progression. Forced ASCL1 expression reversed the tumor-suppressive effects of Norrin in [ASCL1.sup.lo] GSCs. Our results identify Norrin as a modulator of human brain cancer progression and reveal an unanticipated Notch-mediated function of Norrin in regulating cancer stem cell biology. This study identifies an unanticipated role of Norrin in human brain cancer progression. In addition, we provide preclinical evidence suggesting Norrin and canonical Wnt signaling as potential therapeutic targets for GBM subtype-restricted cancer stem cells., Introduction Glioblastoma multiforme (GBM) is the most common malignant brain cancer in adults (1, 2). Consistent with its progressive nature, GBM remains significantly refractory to current therapeutic strategies (3, 4). [...]

The median overall survival of patients with metastatic breast cancer is only 2–3 years, and for patients with untreated liver metastasis, it is as short as 4–8 months. Improving the survival of women with breast cancer requires more effective anti-cancer strategies, especially for metastatic disease. Nutrients can influence tumor microenvironments, and cancer metabolism can be manipulated via a dietary modification to enhance anti-cancer strategies. Yet, there are no standard evidence-based recommendations for diet therapies before or during cancer treatment, and few studies provide definitive data that certain diets can mediate tumor progression or therapeutic effectiveness in human cancer. This review focuses on metastatic breast cancer, in particular liver metastatic forms, and recent studies on the impact of diets on disease progression and treatment. [ABSTRACT FROM AUTHOR]

The study's objective was to determine whether orally ingested caffeine could help overcome excitation-contraction-coupling failure, which has been suggested to explain part of the strength loss associated with eccentric-contraction-induced muscle injury. A sample of 13 college students (4 men and 9 women) was used in a double-blind, repeated-measures experimental design. Each participant performed 2 experimental trials, 1 with each leg, with each trial lasting 4 consecutive days. On a given day, each participant was randomly assigned to ingest a capsule containing 6 mg/kg of either caffeine or flour (placebo). On the day of and the first 2 days after a bout of 50 injurious eccentric contractions done by the knee extensors, the interpolated-twitch technique was used to assess electrically evoked strength, maximal voluntary isometric contraction (MVIC) strength, and percent muscle activation during MVIC both before and after capsule ingestion. These variables were also measured before and after capsule ingestion the day before the eccentric-contraction bout—when the muscle was uninjured. In injured muscle, caffeine had no effect on any variable. In uninjured muscle, caffeine also had no effect on electrically evoked strength but increased MVIC strength by 10.4% compared with placebo (p = .00002), and this was attributed to an increase in muscle activation (6.2%; p = .01). In conclusion, the data provide no evidence that caffeine ingestion can help overcome excitation-contraction-coupling failure, if it exists, in injured human muscle. The data do indicate that caffeine ingestion can increase MVIC strength and activation in uninjured muscle but not in injured muscle. [ABSTRACT FROM AUTHOR]

DiPSI exists to celebrate existing diversity and enhance further polar science opportunities for historically excluded and underrepresented groups such as women, Black, Asian and minority ethnic people, the LGBTQ+ community, people with disabilities or those from lower-socioeconomic backgrounds. The desire for meaningful change led the UK Foreign, Commonwealth and Development Office, Polar Regions Department, to fund the Diversity in UK Polar Science Initiative (DiPSI; https://www.bas.ac.uk/project/diversity-in-uk-polar-science-initiative). [Extracted from the article]

Rehabilitation professionals have a major focus on competitive employment, which is a central component of adult life that provides not only economic benefits, but also a social network and enhanced self-esteem. The employment gap for individuals with disabilities has remained consistently high despite concerted efforts to provide access to quality job readiness training and a simultaneous increase in awareness of the value of diversity in the workforce. This study examined the outcomes of Project SEARCH, an employer-based transition program for young adults with disabilities that promotes partnerships among the school and community by utilizing a unique collaborative approach that brings the education system, employers, and rehabilitation services together to provide meaningful individualized employment experiences for students with disabilities. Findings suggest Project SEARCH appears to have the potential to address employment outcomes for young adults with various disabilities. Implications for practice and future research are also discussed. [ABSTRACT FROM AUTHOR]

Summary Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G 0 /G 1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM. [ABSTRACT FROM AUTHOR]

Summary Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM. [ABSTRACT FROM AUTHOR]

Aims: Genomic sequencing of lymphomas is under-represented in routine clinical testing despite having prognostic and predictive value. Clinical implementation is challenging due to a lack of consensus on reportable targets and a paucity of reference samples. We organised a cross-validation study of a lymphoma-tailored next-generation sequencing panel between two College of American Pathologists (CAP)-accredited clinical laboratories to mitigate these challenges., Methods: A consensus for the genomic targets was discussed between the two institutes based on recurrence in diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and T-cell lymphomas. Using the same genomic targets, each laboratory ordered libraries independently and a cross-validation study was designed to exchange samples (8 cell lines and 22 clinical samples) and their FASTQ files., Results: The sensitivity of the panel when comparing different library preparation and bioinformatic workflows was between 97% and 99% and specificity was 100% when a 5% limit of detection cut-off was applied. To evaluate how the current standards for variant classification of tumours apply to lymphomas, the Association for Molecular Pathology/American Society of Clinical Oncology/CAP and OncoKB classification systems were applied to the panel. The majority of variants were assigned a possibly actionable class or likely pathogenic due to more limited evidence in the literature., Conclusions: The cross-validation study highlights the benefits of sample and data exchange for clinical validation and provided a framework for reporting the findings in lymphoid malignancies., Competing Interests: Competing interests: RK: research funding from AbbVie and travel expenses from Eisai. DWS: Consulting: AbbVie, AstraZeneca, Incyte; Research funding: Janssen, Roche/Genentech; named inventor on patents describing using gene expression to subtype aggressive B-cell lymphomas, including one licensed to NanoString. CSt: Has performed consultancy for Bayer, and has received research funding from Epizyme and Trillium Therapeutics and is a named inventor on a patent filed by the National Cancer Institute 'Methods for determining lymphoma type'., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant as standard of care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared with other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER-targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, lung, and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to fulvestrant. Furthermore, differential ERα activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of fulvestrant treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment., Implications: These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases., (©2022 American Association for Cancer Research.)

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/βcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/βcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/βcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnt hi GBM cells (which exhibit high levels of βcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wnt lo cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/βcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically., (© 2019 Rajakulendran et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Low income postpartum mothers with little to no social support have increased maternal and infant morbidity and mortality, especially those with limited English proficiency and limited accesses to resources. Haitians, a growing minority in the US are an understudied population excluded from most studies due to the lack of instruments in Creole. The most widely used instruments for measuring social support, the Multidimensional Scale of Perceived Social Support (MSPSS) and Perceived Adequacy of Resource Scale (PARS), are not available in Creole. Currently, there are no published studies on the psychometric properties of the MSPSS or the PARS in Creole. Data from Haitian mothers are needed to identify potential postpartum mothers and infants most at risk of developing adverse maternal and infant outcomes from a lack of social support and perceived resources. The purpose of this study is to test the psychometrics of the newly-translated Creole instruments of the MSPSS and PARS with a sample of bilingual (Creole/English) mothers., Methods: The MSPSS and PARS were translated and back translated from English to Creole. The adapted Creole versions of the instruments were tested using a convenience sample. A total of 85 Haitian mothers' completed both instruments in Creole and English 2 weeks apart., Result: Internal consistency reliability and stability were strong for both the MSPSS and PARS (.91-.99). The two instruments had strong reliability and validity for the translated Creole versions and similar to the English versions., Conclusion: The MSPSS and PARS are a valid measure of perceived social support and resources. Psychometric findings suggest that the newly translated Creole versions are good representations of the English versions indicating the translation process was successful. The newly translated instruments available in Creole provide non-English speaking Haitian mothers the opportunity to participate in studies.