Slow art plus: developing and piloting a single session art gallery-based intervention for mental health promotion via a mixed method waitlist randomized control trial.

Introduction: The current study builds on the expertise of National Gallery Singapore and Nanyang Technological University Singapore (NTU) in developing and piloting an enhanced version of the Slow Art program, namely "Slow Art Plus" for mental health promotion. Methods: A single-site, open-label, waitlist Randomized Control Trial (RCT) design comprising of a treatment group and waitlist control group was adopted (ClinicalTrials.gov ID: NCT05803226). Participants (N = 196) completed three online questionnaires at three timepoints: baseline [T1], immediately post-intervention/s baseline [T2], post-intervention follow-up/immediately post-intervention [T3]. Qualitative focus groups were conducted to evaluate program acceptability. Results: A mixed model ANOVA was performed to understand intervention effectiveness between the immediate intervention group and waitlist control group. The analyses revealed a significant interaction effect where intervention group participants reported an improvement in spiritual well-being (p = 0.001), describing their thoughts and experiences (p = 0.02), and nonreacting to inner experiences (p = 0.01) immediately after Slow Art Plus as compared to the control group. Additionally, one-way repeated measure ANOVAs were conducted for the intervention group to evaluate maintenance effects of the intervention. The analyses indicated significant improvements in perceived stress (p < 0.001), mindfulness (p < 0.001) as well as multiple mindfulness subscales, active engagement with the world (p = 0.003), and self-compassion (p = 0.02) 1 day after the completion of Slow Art Plus. Results from framework analysis of focus group data revealed a total of two themes (1: Experiences of Slow Art Plus, 2: Insights to Effective Implementation) and six subthemes (1a: Peaceful relaxation, 1b: Self-Compassion, 1c: Widened Perspective, 2a: Valuable Components, 2b: Execution Requisites, 2c: Suggested Enhancements), providing valuable insights to the overall experience and implementation of the intervention. Discussion: Slow Art Plus represents a unique approach, offering a standardized, multimodal, single-session program that integrates mindfulness and self-compassion practices, as well as reflective and creative expressions with Southeast Asian art. It demonstrates potential in meeting the mental health needs of a wide range of individuals and could be readily incorporated into social prescribing initiatives for diverse populations.

Hallmarks of cancer stemness.

Cancer stemness is recognized as a key component of tumor development. Previously coined "cancer stem cells" (CSCs) and believed to be a rare population with rigid hierarchical organization, there is good evidence to suggest that these cells exhibit a plastic cellular state influenced by dynamic CSC-niche interplay. This revelation underscores the need to reevaluate the hallmarks of cancer stemness. Herein, we summarize the techniques used to identify and characterize the state of these cells and discuss their defining and emerging hallmarks, along with their enabling and associated features. We also highlight potential future directions in this field of research.

Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer.

Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.

Enhanced mitophagy driven by ADAR1-GLI1 editing supports the self-renewal of cancer stem cells in HCC.

BACKGROUND AND AIMS: Deregulation of adenosine-to-inosine editing by adenosine deaminase acting on RNA 1 (ADAR1) leads to tumor-specific transcriptome diversity with prognostic values for HCC. However, ADAR1 editase-dependent mechanisms governing liver cancer stem cell (LCSC) generation and maintenance have remained elusive. APPROACH AND RESULTS: RNA-seq profiling identified ADAR1-responsive recoding editing events in HCC and showed editing frequency of GLI1 , rather than transcript abundance was clinically relevant. Functional differences in LCSC self-renewal and tumor aggressiveness between wild-type (GLI1 wt ) and edited GLI1 (GLI1 edit ) were elucidated. We showed that overediting of GLI1 induced an arginine-to-glycine (R701G) substitution, augmenting tumor-initiating potential and exhibiting a more aggressive phenotype. GLI1 R701G harbored weak affinity to SUFU, which in turn, promoted its cytoplasmic-to-nuclear translocation to support LCSC self-renewal by increased pluripotency gene expression. Moreover, editing predisposed to stabilize GLI1 by abrogating ß-TrCP-GLI1 interaction. Integrative analysis of single-cell transcriptome further revealed hyperactivated mitophagy in ADAR1-enriched LCSCs. GLI1 editing promoted a metabolic switch to oxidative phosphorylation to control stress and stem-like state through PINK1-Parkin-mediated mitophagy in HCC, thereby conferring exclusive metastatic and sorafenib-resistant capacities. CONCLUSIONS: Our findings demonstrate a novel role of ADAR1 as an active regulator for LCSCs properties through editing GLI1 in the highly heterogeneous HCC.

Long Noncoding RNA URB1-Antisense RNA 1 (AS1) Suppresses Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma by Driving Ferritin Phase Separation.

Sorafenib, a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), has been shown to be a potent ferroptosis inducer in HCC. However, we found that there was a lower level of ferroptosis in sorafenib-resistant HCC samples than in sorafenib-sensitive HCC samples, suggesting that sorafenib resistance in HCC may be a result of ferroptosis suppression. Recent reports have shown that long noncoding RNAs (lncRNAs) are involved in programmed cell death (PCD), including apoptosis and ferroptosis. This study aimed to investigate the roles and underlying molecular mechanisms of lncRNAs in sorafenib-induced ferroptosis in HCC cells. Using lncRNA sequencing, we identified a ferroptosis-related lncRNA, URB1-antisense RNA 1 (AS1), which was highly expressed in sorafenib-resistant HCC samples and predicted poor survival in HCC. Furthermore, URB1-AS1 mitigates sorafenib-induced ferroptosis by inducing ferritin phase separation and reducing the cellular free iron content. Hypoxia inducible factor (HIF)-1α was identified as a key factor promoting URB1-AS1 expression in sorafenib-resistant HCC cells. Notably, we found that specifically inhibiting the expression of URB1-AS1 with N-acetylgalactosamine (GalNAc)-small interfering (si)URB1-AS1 successfully enhanced the sensitivity of HCC cells to sorafenib in an in vivo tumor model. Our study uncovered a critical role for URB1-AS1 in the repression of ferroptosis, suggesting URB1-AS1 targeting may represent a potential approach to overcome sorafenib resistance in HCC.

SPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma.

Tumor lineage plasticity, considered a hallmark of cancer, denotes the phenomenon in which tumor cells co-opt developmental pathways to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the underlying molecular events remain largely elusive. Our recent study identified CD133/Prom1 in hepatocellular carcinoma (HCC) tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. Here we show SPINK1 to strongly associate with CD133 + HCC, and tumor dedifferentiation. Enhanced transcriptional activity of SPINK1 is mediated by promoter binding of ELF3, which like CD133, is found to increase following 5-FU and cisplatin treatment; while targeted depletion of CD133 will reduce both ELF3 and SPINK1. Functionally, SPINK1 overexpression promotes tumor initiation, self-renewal, and chemoresistance by driving a deregulated EGFR-ERK-CDK4/6-E2F2 signaling axis to induce dedifferentiation of HCC cells into their ancestral lineages. Depleting SPINK1 function by neutralizing antibody treatment or in vivo lentivirus-mediated Spink1 knockdown dampens HCC cancer growth and their ability to resist chemotherapy. Targeting oncofetal SPINK1 may represent a promising therapeutic option for HCC treatment.

Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma.

Increasing evidence has demonstrated that drug resistance can be acquired in cancer cells by kinase rewiring, which is an obstacle for efficient cancer therapy. However, it is technically challenging to measure the expression of protein kinases on large scale due to their dynamic range in human proteome. We employ a lysine-targeted sulfonyl fluoride probe, named XO44, which binds to 133 endogenous kinases in intact lenvatinib-resistant hepatocellular carcinoma (HCC) cells. This analysis reveals cyclin-dependent kinase 6 (CDK6) upregulation, which is mediated by ERK/YAP1 signaling cascade. Functional analyses show that CDK6 is crucial in regulation of acquired lenvatinib resistance in HCC via augmentation of liver cancer stem cells with clinical significance. We identify a noncanonical pathway of CDK6 in which it binds and regulates the activity of GSK3ß, leading to activation of Wnt/ß-catenin signaling. Consistently, CDK6 inhibition by palbociclib or degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with lenvatinib in vitro. Interestingly, palbociclib not only exerts maximal growth suppressive effect with lenvatinib in lenvatinib-resistant HCC models but also reshapes the tumor immune microenvironment. Together, we unveil CDK6 as a druggable target in lenvatinib-resistant HCC and highlight the use of a chemical biology approach to understand nongenetic resistance mechanisms in cancer.

ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer.

Targetable drivers governing 5-fluorouracil and cisplatin (5FU + CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Here, we establish 5FU + CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 confers chemoresistance and self-renewal in an RNA editing-dependent manner. WES coupled with RNA-seq identify enrichment of hyper-edited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3'UTR of stearoyl-CoA desaturase (SCD1) increases binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing ß-catenin expression. Pharmacological inhibition of SCD1 abrogates chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveil a potential target to circumvent chemoresistance.

Experimental models for preclinical cancer research.

The devastating disease of human cancers is a global health concern. In the past, development of effective therapies has been hindered by a shortage of reliable models; but in recent years, experimental models of human cancer for research are becoming more sophisticated. In this special issue consisting of series of seven short reviews, investigators working on different cancer types and experimental models summarize updated knowledge and present perspectives on some of the recent progress in human cancer modeling. Specifically, modeling leukemia, breast, ovarian and liver cancers by zebrafish, mouse and organoids are reviewed, with their strengths and limitations highlighted.

SERPINA12 promotes the tumorigenic capacity of HCC stem cells through hyperactivation of AKT/ß-catenin signaling.

BACKGROUND AND AIMS: HCC is an aggressive disease with poor clinical outcome. Understanding the mechanisms that drive cancer stemness, which we now know is the root cause of therapy failure and tumor recurrence, is fundamental for designing improved therapeutic strategies. This study aims to identify molecular players specific to CD133 + HCC to better design drugs that can precisely interfere with cancer stem cells but not normal stem cell function. APPROACH AND RESULTS: Transcriptome profiling comparison of epithelial-specific "normal" CD133 + cells isolated from fetal and regenerating liver against "HCC" CD133 + cells isolated from proto-oncogene-driven and inflammation-associated HCC revealed preferential overexpression of SERPINA12 in HCC but not fetal and regenerating liver CD133 + cells. SERPINA12 upregulation in HCC is tightly associated with aggressive clinical and stemness features, including survival, tumor stage, cirrhosis, and stemness signatures. Enrichment of SERPINA12 in HCC is mediated by promoter binding of the well-recognized ß-catenin effector TCF7L2 to drive SERPINA12 transcriptional activity. Functional characterization identified a unique and novel role of endogenous SERPINA12 in promoting self-renewal, therapy resistance, and metastatic abilities. Mechanistically, SERPINA12 functioned through binding to GRP78, resulting in a hyperactivated AKT/GSK3ß/ß-catenin signaling cascade, forming a positive feed-forward loop. Intravenous administration of rAAV8-shSERPINA12 sensitized HCC cells to sorafenib and impeded the cancer stem cell subset in an immunocompetent HCC mouse model. CONCLUSIONS: Collectively, our findings revealed that SERPINA12 is preferentially overexpressed in epithelial HCC CD133 + cells and is a key contributor to HCC initiation and progression by driving an AKT/ß-catenin feed-forward loop.

M6PR- and EphB4-Rich Exosomes Secreted by Serglycin-Overexpressing Esophageal Cancer Cells Promote Cancer Progression.

Accumulating evidence shows that exosomes participate in cancer progression. However, the functions of cancer cell exosome-transmitted proteins are rarely studied. Previously, we reported that serglycin (SRGN) overexpression promotes invasion and metastasis of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the paracrine effects of exosomes from SRGN-overexpressing ESCC cells (SRGN Exo) on ESCC cell invasion and tumor angiogenesis, and used mass spectrometry to identify exosomal proteins involved. Cation-dependent mannose-6-phosphate receptor (M6PR) and ephrin type-B receptor 4 (EphB4) were pronouncedly upregulated in SRGN Exo. Upregulated exosomal M6PR mediated the pro-angiogenic effects of SRGN Exo both in vitro and in vivo, while augmented exosomal EphB4 mediated the pro-invasive effect of SRGN Exo on ESCC cells in vitro. In addition, in vitro studies showed that manipulation of M6PR expression affected the viability and migration of ESCC cells. Both M6PR and EphB4 expression levels were positively correlated with that of SRGN in the serum of patients with ESCC. High level of serum M6PR was associated with poor overall survival rates. Taken together, this study presents the first proof that exosomal M6PR and EphB4 play essential roles in tumor angiogenesis and malignancy, and that serum M6PR is a novel prognostic marker for ESCC patients.

Escape from cell-cell and cell-matrix adhesion dependence underscores disease progression in gastric cancer organoid models.

OBJECTIVE: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. DESIGN: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. RESULTS: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. CONCLUSIONS: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

Noncellular components in the liver cancer stem cell niche: Biology and potential clinical implications.

Cancer stem cells (CSCs) are now recognized as one of the major root causes of therapy failure and tumor recurrence in hepatocellular carcinoma (HCC). Early studies in the field focused primarily on the intrinsic regulators of CSC maintenance, but in recent years, mounting evidence has demonstrated the presence and role of extrinsic regulators in the tumor microenvironment (TME) in the control of liver CSCs. In addition to direct interaction with cellular components, noncellular components, including the extracellular matrix, hypoxia, nutrient deprivation, and secreted molecules within the tumor stroma and hepatitis viruses, also play a critical role in shaping the CSC niche. In this review, we highlight how various noncellular components in the TME play a role in regulating CSCs and how CSCs secrete components to interact with the TME to generate their own niche, working hand in hand to drive tumor physiology in HCC. In addition, we describe the potential clinical applications of these findings and propose perspectives on future research of noncellular components in the liver CSC niche.

SCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression.

Background & Aims: SCY1-like pseudokinase 3 (SCYL3) was identified as a binding partner of ezrin, implicating it in metastasis. However, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. In this study, we aimed to elucidate the role of SCYL3 in the progression of hepatocellular carcinoma (HCC). Methods: The clinical significance of SCYL3 in HCC was evaluated in publicly available datasets and by qPCR analysis of an in-house HCC cohort. The functional significance and mechanistic consequences of SCYL3 were examined in SCYL3-knockdown/overexpressing HCC cells. In vivo tumor progression was evaluated in Tp53 KO/c-Myc OE mice using the sleeping beauty transposon system. Potential downstream pathways were investigated by co-immunoprecipitation, western blotting analysis and immunofluorescence staining. Results: SCYL3 is often overexpressed in HCC; it is preferentially expressed in metastatic human HCC tumors and is associated with worse patient survival. Suppression of SCYL3 in HCC cells attenuated cell proliferation and migration as well as in vivo metastasis. Intriguingly, endogenous SCYL3 overexpression increased tumor development and metastasis in Tp53 KO/c-Myc OE mice. Mechanistic investigations revealed that SCYL3 physically binds and regulates the stability and transactivating activity of ROCK2 (Rho kinase 2) via its C-terminal domain, leading to the increased formation of actin stress fibers and focal adhesions. Conclusions: These findings reveal that SCYL3 plays a critical role in promoting the progression of HCC and have implications for developing new therapeutic strategies to tackle metastatic HCC. Impact and implications: SCYL3 was first reported to be a binding partner of a metastasis-related gene, ezrin. To date, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. Herein, we uncover its crucial role in liver cancer progression. We show that it physically binds and regulates the stability and transactivating activity of ROCK2 leading to HCC tumor progression. Our data provide mechanistic insight that SCYL3-mediated ROCK2 protein stability plays a pivotal role in growth and metastasis of HCC cells. Targeting SCYL3/ROCK2 signaling cascade may be a novel therapeutic strategy for treatment of HCC patients.

Protein Tyrosine Kinase 7 (PTK7) Promotes Metastasis in Hepatocellular Carcinoma via SOX9 Regulation and TGF-ß Signaling.

BACKGROUND & AIMS: Metastasis is found in most advanced hepatocellular carcinoma (HCC) patients, and it drives tumor recurrence and systemic failure. There is no effective treatment owing to its complex biological features. Many of the molecular drivers of metastasis are crucial players in normal physiology but behave unconventionally during cancer progression. Targeting these molecular drivers for therapy and differentiating them from a physiological background require a detailed examination of the novel mechanisms involved in their activation during metastasis. METHODS: Publicly available transcriptomic data such as that of TCGA-LIHC and Gene Expression Omnibus were utilized to identify novel targets upregulated in advanced and metastatic HCC. Validation of candidates was assisted by immunohistochemistry performed on tissue microarrays derived from more than 100 HCC patients. Expression of protein tyrosine kinase 7 (PTK7) was studied under the treatment of transforming growth factor-ß1 and knockdown of SRY-Box Transcription Factor 9 (SOX9) to delineate upstream regulation, while CRISPR-mediated knockout and lentiviral overexpression of PTK7 in HCC cells were performed to study their functional and signaling consequences. Manipulated HCC cells were injected into mice models either by orthotopic or tail-vein injection to observe for any in vivo pro-metastatic effects. RESULTS: PTK7 was discovered to be the kinase most significantly upregulated in advanced and metastatic HCC, at both transcriptomic and proteomic level. Bioinformatic analyses and functional assays performed in HCC cell lines revealed transforming growth factor-ß signaling and SOX9 to be important activators of PTK7 expression. Functionally, enrichment of PTK7 expression could positively regulate metastatic potential of HCC cells in vitro and in lung metastasis models performed in immunodeficient mice. The up-regulation of PTK7 recruited the epithelial-mesenchymal transition components, zinc finger protein SNAI2 (SLUG) and zinc finger E-box-binding homeobox 1 (ZEB1). CONCLUSIONS: Our study proposes PTK7 as a novel molecular driver in metastatic HCC, particularly in a transforming growth factor-ß-activated microenvironment. The preferential expression of PTK7 resulted in a previously unobserved regulatory effect on the recruitment of epithelial-mesenchymal transition components, which established PTK7 as a potential determinant of specific epithelial-mesenchymal transition status. Therefore, our data support the continual development of PTK7-targeted agents as antimetastatic therapies.

Effects of participatory 'A'rt-Based Activity On 'Health' of Older Community-Dwellers: results from a randomized control trial of the Singapore A-Health Intervention.

Introduction: The practice of participatory art has been found to support the promotion, prevention, and management of health across the lifespan. However, clinical trials investigating the benefits of creative activities curated with and conducted in museums among older adults in East Asia remains limited. Methods: The current research utilized a single-site, open-label randomized control trial (RCT) to evaluate a standardized Participatory 'A'rt-Based Activity On 'Health' of Older Community-Dwellers - the Singapore A-Health Intervention. Outcome measures include frailty as assessed by the Centre of Excellence on Longevity Self-administered Questionnaire, wellbeing as assessed by the Warwick-Edinburgh Mental Wellbeing Scales, and quality of life as assessed by the EuroQol-5D. 112 participants aged 60 and above were randomized into the intervention group (n = 56) or an inactive control group (n = 56). Participants completed four standardized online self-administered assessments at baseline, 5-week, 9-week and 12-week follow-up during the intervention period. Results: Linear mixed model analyses revealed no statistically significant differences between the intervention group and control group for all outcome measures. However, within the intervention group, a consistent significant reduction in frailty was observed across time from baseline to 9 weeks (MD -0.44, 95% CI -0.85 to -0.039, p = 0.032), 5-weeks to 9-weeks (MD -0.64, 95% CI -1.03 to -0.24, p = 0.002), and 5-weeks to 12-weeks (MD -0.51, 95% CI -0.91 to -0.10, p = 0.014). Moreover, the post-test mean wellbeing score in the intervention group significantly improved over time at 9-weeks (MD 1.65, 95% CI 0.09 to 3.22, p = 0.039) and 12-week (MD 2.42, 95% CI 0.67 to 4.16, p = 0.006) as compared to baseline scores. Discussion: The findings demonstrate the potential of a structured art and museum-based intervention as a resource for promoting health among aging populations. Such benefits transcend social, cultural, and societal contexts. Clinical trial registration: ClinicalTrial.gov, NCT05945589.

A qualitative examination on the implementation of participatory "A"rt-based activity on "Health" of older community-dwellers: what worked for the Singapore A-Health Intervention?

Introduction: Art and museum-based interventions are gaining increasing recognition for their potential as low-risk activities for older adults, offering numerous physical, cognitive, and emotional benefits. However, there remains a dearth of knowledge regarding the science of implementation as well as the factors and processes that contribute to their effectiveness from the perspectives of intervention participants. Methods: The current research draws on the qualitative evaluation data obtained from a larger mixed-method randomized control trial that evaluated a standardized Participatory "A"rt-Based Activity On "Health" of Older Community-Dwellers-the Singapore A-Health Intervention. Adopting a participatory action research approach, the primary objective is to critically examine the lived experiences and health impact of the Singapore A-Health Intervention with a secondary objective to uncover strategies for optimized implementation outcomes. All 56 participants who completed the intervention filled out a program evaluation survey and a nested sample of 30 participants completed a series of acceptability focus groups. Results: Descriptive analyses of the program evaluation survey data revealed that 96.2% of participants were satisfied with the overall experience of the Singapore A-Health intervention (M = 9.00, SD = 1.76), reported that the intervention positively impacted their quality of life (M = 8.90, SD = 1.43), and social wellbeing (M = 8.92, SD = 1.43). Thematic analysis with a grounded theory approach on the qualitative focus group data revealed three interrelated themes detailing how the Singapore A-Health Intervention contributed to positive health and wellbeing outcomes (1. A-Health Experience, 2. Wellbeing Outcomes, 3. Enabling Factors) and nine subthemes (1a. Intellectual Stimulation, 1b. Positive Stress, 1c. Peer Interaction, 2a. Interpersonal Bonds, 2b. Personal Growth, 2c. Mindful Living, 3a. Integrated Support, 3b. Session Design, 3c. Mode of Engagement). Discussion: This investigation provides important insights to the Singapore A-Health intervention's effectiveness for enhancing wellbeing among older adults, as well as the factors that enable successful program implementation. These findings offer a culturally unique perspective on the benefits of art and museum interventions, while underscoring the imperative need for strong partnership and collaborations among community stakeholders in supporting the health and wellbeing of ageing populations.

Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy.

Identifying signals that govern the differentiation of tumor-infiltrating CD8+ T cells (CD8+ TILs) toward exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues, enhancing terminal CD8+ T cell exhaustion in tumors. We find enrichment of IFN-I-stimulated genes (ISGs) within exhausted CD8+ T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8+ TILs devoid of IFN-I signaling develop less exhaustion features, provide better tumor control, and show greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-I stimulation perturbs lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promote lipid peroxidation, which potentiates metabolic and functional exhaustion of Tex cells. Thus, cell-intrinsic IFN-I signaling regulates the extent of CD8+ TIL exhaustion and has important implications for immunotherapy.