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Introduction: Post-implantation rod deformation is anticipated in scoliosis surgery but the difference in rod deformation between titanium and cobalt chrome rod has not been elucidated. This study aims to compare the difference in rod deformation between two groups. Materials and Methods: Twenty-one adolescent idiopathic scoliosis (AIS) patients were recruited from a single center. The over-contoured concave rods were traced prior to insertion. Post-operative sagittal rod shape was determined from lateral radiographs. Rod deformation was determined using maximal rod deflection and angle of the tangents to rod end points. The differences between pre- and post-operative rod contour were analysed statistically. Rod deformation and thoracic kyphosis between two types of implants were analysed. Results: Both rods exhibited significant change of rod angle and deflection post-operatively. Curvature of the titanium rod and cobalt chrome rod decreased from 60.5° to 37°, and 51° to 28° respectively. Deflection of titanium rod and cobalt chrome rod reduced from 28mm to 23.5mm and 30mm to 17mm respectively. There was no significant difference between titanium and cobalt chrome groups with regard to rod angle (p=0.173) and deflection (p=0.654). Thoracic kyphosis was increased from 20° to 26° in titanium group but a reduction from 25° to 23° was noticed in cobalt chrome group, but these findings were not statistically significant. Conclusion: There was no statistical difference in rod deformation between the two groups. Thus, the use of titanium rod in correction of sagittal profile is not inferior in outcome compared with cobalt chrome but with lower cost.

Giant cell tumour (GCT) is a benign tumour but can be locally aggressive and with the potential to metastasise especially to the lungs. Successful treatments have been reported for long bone lesions; however, optimal surgical and medical treatment for spinal and sacral lesions are not well established. In treating spinal GCTs, the aim is to achieve complete tumour excision, restore spinal stability and decompress the neural tissues. The ideal surgical procedure is an en bloc spondylectomy or vertebrectomy, where all tumour cells are removed as recurrence is closely related to the extent of initial surgical excision. However, such a surgery has a high complication rate, such as dura tear and massive blood loss. We report a patient with a missed pathological fracture of T12 treated initially with a posterior subtraction osteotomy, who had recurrence three years after the index surgery and subsequently underwent a three level vertebrectomy and posterior spinal fusion.

Piaopiao Jin,1,2 Chi Chun Wong,3 Sibin Mei,1 Xingkang He,4 Yun Qian,4 Leimin Sun1 1Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 2Department of Gastroenterology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 3Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, 4Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Abstract: The anticancer effect of MK-2206, an Akt inhibitor, has been explored in some types of cancers, but its effect on gastric cancer is unclear. In this study, we aimed to investigate its anticancer effect in gastric cancer cells. Cell viability and colony formation assays showed that MK-2206 effectively inhibited the proliferation of SGC-7901 and MKN45 cells. The 50% inhibitory concentration values after 24, 48, and 72 hours’ treatment were 22.92, 13.68, and 8.55 µM in SGC-7901 cells and 19.21, 13.10, and 9.11 µM in MKN45 cells, respectively. Treatment with MK-2206 induced apoptosis in SGC-7901 cells as indicated by flow cytometry assay. The combination indexes of MK-2206 and doxorubicin were 0.59 in SGC-7901 cells and 0.57 in MKN45 cells, whereas for 5-fluorouracil (5-FU) the indexes were 0.17 in SGC-7901 cells and 0.73 in MKN45 cells, indicating that MK-2206 could work synergistically with doxorubicin or 5-FU to inhibit cell growth. Furthermore, a small dose (1 µM) of MK-2206 co-treatment with doxorubicin or 5-FU was sufficient for complete inhibition of chemotherapeutic alteration of phosphorylated Akt expression and significant enhancement of pro-apoptosis effect through the activation of caspase pathway. Therefore, MK-2206 effectively inhibits gastric cancer cell growth by attenuation of Akt phosphorylation and synergistically enhances the antitumor effect of doxorubicin and 5-FU via caspase-dependent apoptosis. Keywords: MK-2206, Akt pathway, apoptosis, chemotherapy, caspase, gastric cancer

Breakage of the tip of the micropituitary forceps during spine surgery is a rare occurrence. Retrieval of the broken tip could be a challenge in minimally invasive surgeries due to limitation of access and retrieval instruments. We describe our experience in handling such a situation during percutaneous radiofrequency discectomy. The removal was attempted, without converting into open surgery, by utilising percutaneous endoscopic lumbar discectomy working cannula and guided by image intensifier. We were able to remove the fragment without any significant morbidity to the patient. This technique for removal has not been reported previously in the literature.

Cyrus C Wong, Matthew J McGirt Vanderbilt University Medical Center, Nashville, TN, USA Abstract: Vertebral compression fractures are a prevalent disease affecting osteoporotic patients. When symptomatic, they cause significant pain and loss of function and have a high public health impact. In this paper we outline the diagnosis and management of these patients, with evidence-based review of treatment outcomes for the various therapeutic options. Diagnosis involves a clinical history focusing on the nature of the patient's pain as well as various imaging studies. Management is multimodal in nature and starts with conservative therapy consisting of analgesic medication, medication for osteoporosis, physical therapy, and bracing. Patients who are refractory to conservative management may be candidates for vertebral augmentation through either vertebroplasty or kyphoplasty. Keywords: vertebral compression fractures, osteoporosis, bracing, vertebroplasty, kyphoplasty

The development and validation of a new instrument for measuring the descriptive norms related to individualism-collectivism (IC) is presented. Ie is conceptualized as a groupspecific unidimensional cultural construct with four defining attributes (Triandis, 1995). Three studies are reported showing the dimensionality and validities at individual and cultural levels across samples from II cultures. The new instrument has good statistical properties with identical structures at the individual and cultural level, good reliabilities at the individual level, adequate agreement within cultures, and demonstrates first signs of convergent and discriminant validity. Correlations at the cultural level also indicate that the measure has the potential to add to research by integrating previously untapped attributes of Ie. Finally, normative IC explains variance in self-reported behavior over and above self-referenced Ie. Implications and opportunities for norm-oriented research and scale refinement are discussed. [ABSTRACT FROM AUTHOR]

To assess contexts of adherence with hypertension care among Hmong Americans, in-person interviews were conducted with a convenience sample of 323 adults using culturally adapted survey instruments. The mean age of participants was 58 years; 91% had no education, and 86% spoke no English. Although more than 90% had health insurance and were treated with medications, the rate of blood pressure control was low (27%). A majority (> 90%) suffered from psychological distress, and 46% lived with physical illness. Over 50% reported nonadherence with hypertension care. Respondents who were 50 years of age or older, had no physical illness, did not know that hypertension was preventable, or believed that American medicine was too strong, were more likely to report nonadherence with proper medication consumption. Findings suggest that adherence was not due to lack of health care coverage; instead, it may be due to gaps in health services. [ABSTRACT FROM AUTHOR]

The N6-methyladenosine (m6A) RNA-binding protein YTHDF1 is frequently overexpressed in colorectal cancer and drives chemotherapeutic resistance. To systematically identify druggable targets in colorectal cancer with high expression of YTHDF1, this study used a CRISPR/Cas9 screening strategy that revealed RUVBL1 and RUVBL2 as putative targets. RUVBL1/2 were overexpressed in primary colorectal cancer samples and represented independent predictors of poor patient prognosis. Functionally, loss of RUVBL1/2 preferentially impaired the growth of YTHDF1-high colorectal cancer cells, patient-derived primary colorectal cancer organoids, and subcutaneous xenografts. Mechanistically, YTHFD1 and RUVBL1/2 formed a positive feedforward circuit to accelerate oncogenic translation. YTHDF1 bound to m6A-modified RUVBL1/2 mRNA to promote translation initiation and protein expression. Coimmunoprecipitation and mass spectrometry identified that RUVBL1/2 reciprocally interacted with YTHDF1 at 40S translation initiation complexes. Consequently, RUVBL1/2 depletion stalled YTHDF1-driven oncogenic translation and nascent protein biosynthesis, leading to proliferative arrest and apoptosis. Ribosome sequencing revealed that RUVBL1/2 loss impaired the activation of MAPK, RAS, and PI3K-AKT signaling induced by YTHDF1. Finally, the blockade of RUVBL1/2 by the pharmacological inhibitor CB6644 or vesicle-like nanoparticle-encapsulated siRNAs preferentially arrested the growth of YTHDF1-expressing colorectal cancer in vitro and in vivo. Our findings show that RUVBL1/2 are potential prognostic markers and druggable targets that regulate protein translation in YTHDF1-high colorectal cancer. Significance: RUVBL1/2 inhibition is a therapeutic strategy to abrogate YTHDF1-driven oncogenic translation and overcome m6A dysregulation in colorectal cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Hepatocellular carcinoma (HCC), the major type of primary liver cancer, is notorious for its resistance to systemic treatments. The field has made a great leap in the past decade, with the number of FDA-approved therapies for advanced HCC increasing from 1 to 9. Although tyrosine kinase inhibitors remain the most common first-line option as monotherapy treatment, the clinical success of immune checkpoint inhibitors, especially when used in combination with anti-VEGF/VEGFR in HCC will likely transform the treatment landscape. While immune checkpoint inhibitors represent an exciting therapeutic revenue for HCC, recent studies have revealed that nonviral HCC, which is primarily caused by metabolic dysfunction-associated steatotic hepatitis (MASH), has a distinct and less favorable response to the immune checkpoint inhibitors. MASH is the most rapidly increasing etiology for HCC. The immune microenvironment of MASH-HCC is greatly affected by the intertwined pathological processes of steatosis-induced iterative cycles between steatohepatitis and liver injury. Here, we present a timely summary of the immune microenvironment of MASH-HCC. We will delve into the use of cutting-edge technologies, such as single-cell RNA sequencing, spatial transcriptomics, and mass cytometry imaging, to deconvolute the complexity of the immune ecosystem in MASH-HCC. We will also discuss the novel therapeutic innovations for MASH-HCC in preclinical models, such as the metabolic inhibitor, epigenetic inhibitor, and immunomodulator. These inhibitors all have the ability to subvert the immune microenvironment of MASH-HCC, improving the efficiency of anti-PD-1. While awaiting new drugs to be tested in clinical trials, the knowledge gained from these investigations is crucial for the development of personalized and effective treatment strategies for MASH-HCC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Segmental bone defects can arise from trauma, infection, metabolic bone disorders, or tumor removal. Hydrogels have gained attention in the field of bone regeneration due to their unique hydrophilic properties and the ability to customize their physical and chemical characteristics to serve as scaffolds and carriers for growth factors. However, the limited mechanical strength of hydrogels and the rapid release of active substances have hindered their clinical utility and therapeutic effectiveness. With ongoing advancements in material science, the development of injectable and biofunctionalized hydrogels holds great promise for addressing the challenges associated with segmental bone defects. In this study, we incorporated lyophilized platelet-rich fibrin (LPRF), which contains a multitude of growth factors, into a genipin-crosslinked gelatin/hyaluronic acid (GLT/HA-0.5 % GP) hydrogel to create an injectable and biofunctionalized composite material. Our findings demonstrate that this biofunctionalized hydrogel possesses optimal attributes for bone tissue engineering. Furthermore, results obtained from rabbit model with segmental tibial bone defects, indicate that the treatment with this biofunctionalized hydrogel resulted in increased new bone formation, as confirmed by imaging and histological analysis. From a translational perspective, this biofunctionalized hydrogel provides innovative and bioinspired capabilities that have the potential to enhance bone repair and regeneration in future clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Coronary disease complexity is commonly used to guide revascularization strategy in patients with multivessel disease (MVD)., Objectives: The aim of this study was to assess the interactive effects of coronary complexity on percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) outcomes and identify the optimal threshold at which PCI can be considered a reasonable option., Methods: A total of 1,444 of 1,500 patients with MVD from the FAME (Fractional Flow Reserve versus Angiography for Multi-vessel Evaluation) 3 randomized trial were included in the analysis (710 CABG vs 734 PCI). SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) scores were transformed into restricted cubic splines, and logistic regression models were fitted, with multiplicative interaction terms for revascularization strategy. Optimal thresholds at which PCI is a reasonable alternative to CABG were determined on the basis of Cox regression model performance., Results: The mean SYNTAX score (SS) was 25.9 ± 7.1. SS was associated with 1-year major adverse cardiac and cerebrovascular events among PCI patients and 3-year death, myocardial infarction, and stroke among CABG patients. Significant interactions were present between revascularization strategy and SS for 1- and 3-year composite endpoints (P for interaction <0.05 for all). In Cox regression models, outcomes were comparable between CABG and PCI for the 3-year primary endpoint for SS ≤24 (P = 0.332), with 44% of patients below this threshold and 32% below the conventional SS threshold of ≤22., Conclusions: In patients with MVD without left main disease, PCI and CABG outcomes remain comparable up to SS values in the mid- rather than low 20s, which allows the identification of a greater proportion of patients in whom PCI may be a reasonable alternative to CABG., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from Medtronic and Abbott Vascular. Dr Dawson is supported by the Australian National Health and Medical Research Council and the Australian National Heart Foundation postgraduate scholarships. Dr Kobayashi serves as a consultant for Abbott Vascular. Dr Fearon has received institutional research support from Abbott Vascular, and Medtronic; and has stock options with HeartFlow. Dr De Bruyne has consulting relationships with Boston Scientific, Abbott Vascular, CathWorks, Siemens, and Coroventis Research; has received research grants from Abbott Vascular, Coroventis Research, CathWorks, and Boston Scientific; and holds minor equities in Philips-Volcano, Siemens, GE Healthcare, Edwards Lifesciences, HeartFlow, Sanofi, and Celyad. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This study proposes a method named Hybrid Heuristic Proximal Policy Optimization (HHPPO) to implement online 3D bin-packing tasks. Some heuristic algorithms for bin-packing and the Proximal Policy Optimization (PPO) algorithm of deep reinforcement learning are integrated to implement this method. In the heuristic algorithms for bin-packing, an extreme point priority sorting method is proposed to sort the generated extreme points according to their waste spaces to improve space utilization. In addition, a 3D grid representation of the space status of the container is used, and some partial support constraints are proposed to increase the possibilities for stacking objects and enhance overall space utilization. In the PPO algorithm, some heuristic algorithms are integrated, and the reward function and the action space of the policy network are designed so that the proposed method can effectively complete the online 3D bin-packing task. Some experimental results illustrate that the proposed method has good results in achieving online 3D bin-packing tasks in some simulation environments. In addition, an environment with image vision is constructed to show that the proposed method indeed enables an actual robot manipulator to successfully and effectively complete the bin-packing task in a real environment.

Peptostreptococcus stomatis (P. stomatis) is enriched in colorectal cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that P. stomatis accelerates colonic tumorigenesis in Apc Min/+ and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing apoptosis, and impairing gut barrier function. P. stomatis adheres to CRC cells through its surface protein fructose-1,6-bisphosphate aldolase (FBA) that binds to the integrin α6/β4 receptor on CRC cells, leading to the activation of ERBB2 and the downstream MEK-ERK-p90 cascade. Blockade of the FBA-integrin α6/β4 abolishes ERBB2-mitogen-activated protein kinase (MAPK) activation and the protumorigenic effect of P. stomatis. P. stomatis-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. P. stomatis also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAF V600E -mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Changes in plasma and fecal metabolomes in colorectal cancer (CRC) progression (normal-adenoma-CRC) remain unclear. Here, plasma and fecal samples were collected from four independent cohorts of 1,251 individuals (422 CRC, 399 colorectal adenoma [CRA], and 430 normal controls [NC]). By metabolomic profiling, signature plasma and fecal metabolites with consistent shift across NC, CRA, and CRC are identified, including CRC-enriched oleic acid and CRC-depleted allocholic acid. Oleic acid exhibits pro-tumorigenic effects in CRC cells, patient-derived organoids, and two murine CRC models, whereas allocholic acid has opposing effects. By integrative analysis, we found that oleic acid or allocholic acid directly binds to α-enolase or farnesoid X receptor-1 in CRC cells, respectively, to modulate cancer-associated pathways. Clinically, we establish a panel of 17 plasma metabolites that accurately diagnoses CRC in a discovery and three validation cohorts (AUC = 0.848-0.987). Overall, we characterize metabolite signatures, mechanistic significance, and diagnostic potential of plasma and fecal metabolomes in CRC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Adenosine-to-Inosine (A-to-I), one of the most prevalent RNA modifications, has recently garnered significant attention. The A-to-I modification actively contributes to biological and pathological processes by affecting the structure and function of various RNA molecules, including double stranded RNA, transfer RNA, microRNA, and viral RNA. Increasing evidence suggests that A-to-I plays a crucial role in the development of human disease, particularly in cancer, and aberrant A-to-I levels are closely associated with tumorigenesis and progression through regulation of the expression of multiple oncogenes and tumor suppressor genes. Currently, the underlying molecular mechanisms of A-to-I modification in cancer are not comprehensively understood. Here, we review the latest advances regarding the A-to-I editing pathways implicated in cancer, describing their biological functions and their connections to the disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.)

Cancer is a leading cause of death worldwide. Around one-third of the total global cancer incidence and mortality are related to gastrointestinal (GI) cancers. Over the past few years, rapid developments have been made in patient-derived organoid (PDO) models for gastrointestinal cancers. By closely mimicking the molecular properties of their parent tumors in vitro, PDOs have emerged as powerful tools in personalized medicine and drug discovery. Here, we review the current literature on the application of PDOs of common gastrointestinal cancers in the optimization of drug treatment strategies in the clinic and their rising importance in pre-clinical drug development. We discuss the advantages and limitations of gastrointestinal cancer PDOs and outline the microfluidics-based strategies that improve the throughput of PDO models in order to extract the maximal benefits in the personalized medicine and drug discovery process.

Background Lutetium 177 [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) is a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC). Quantitative PSMA PET/CT analysis could provide information on 177 Lu-PSMA-617 treatment benefits. Purpose To explore the association between quantitative baseline gallium 68 [ 68 Ga]Ga-PSMA-11 ( 68 Ga-PSMA-11) PET/CT parameters and treatment response and outcomes in the VISION trial. Materials and Methods This was an exploratory secondary analysis of the VISION trial. Eligible participants were randomized (June 2018 to October 2019) in a 2:1 ratio to 177 Lu-PSMA-617 therapy (7.4 GBq every 6 weeks for up to six cycles) plus standard of care (SOC) or to SOC only. Baseline 68 Ga-PSMA-11 PET parameters, including the mean and maximum standardized uptake value (SUV mean and SUV max ), PSMA-positive tumor volume, and tumor load, were extracted from five anatomic regions and the whole body. Associations of quantitative PET parameters with radiographic progression-free survival (rPFS), overall survival (OS), objective response rate, and prostate-specific antigen response were investigated using univariable and multivariable analyses (with treatment as the only other covariate). Outcomes were assessed in subgroups based on SUV mean quartiles. Results Quantitative PET parameters were well balanced between study arms for the 826 participants included. The median whole-body tumor SUV mean was 7.6 (IQR, 5.8-9.9). Whole-body tumor SUV mean was the best predictor of 177 Lu-PSMA-617 efficacy, with a hazard ratio (HR) range of 0.86-1.43 for all outcomes (all P < .001). A 1-unit whole-body tumor SUV mean increase was associated with a 12% and 10% decrease in risk of an rPFS event and death, respectively. 177 Lu-PSMA-617 plus SOC prolonged rPFS and OS in all SUV mean quartiles versus SOC only, with no identifiable optimum among participants receiving 177 Lu-PSMA-617. Higher baseline PSMA-positive tumor volume and tumor load were associated with worse rPFS (HR range, 1.44-1.53 [ P < .05] and 1.02-1.03 [ P < .001], respectively) and OS (HR range, 1.36-2.12 [ P < .006] and 1.04 [ P < .001], respectively). Conclusion Baseline 68 Ga-PSMA-11 PET/CT whole-body tumor SUV mean was the best predictor of 177 Lu-PSMA-617 efficacy in participants in the VISION trial. Improvements in rPFS and OS with 177 Lu-PSMA-617 plus SOC were greater among participants with higher whole-body tumor SUV mean , with evidence for benefit at all SUV mean levels. ClinicalTrials.gov identifier: NCT03511664 Published under a CC BY 4.0 license. Supplemental material is available for this article.

Background and Aims: Chromatin assembly factor 1 (CAF-1) is a replication-dependent epigenetic regulator that controls cell cycle progression and chromatin dynamics. In this study, we aim to investigate the immunomodulatory role and therapeutic potential of the CAF-1 complex in HCC., Approach and Results: CAF-1 complex knockout cell lines were established using the CRISPR/Cas9 system. The effects of CAF-1 in HCC were studied in HCC cell lines, nude mice, and immunocompetent mice. RNA-sequencing, ChIP-Seq, and assay for transposase accessible chromatin with high-throughput sequencing (ATAC-Seq) were used to explore the changes in the epigenome and transcriptome. CAF-1 complex was significantly upregulated in human and mouse HCCs and was associated with poor prognosis in patients with HCC. Knockout of CAF-1 remarkably suppressed HCC growth in both in vitro and in vivo models. Mechanistically, depletion of CAF-1 induced replicative stress and chromatin instability, which eventually led to cytoplasmic DNA leakage as micronuclei. Also, chromatin immunoprecipitation sequencing analyses revealed a massive H3.3 histone variant replacement upon CAF-1 knockout. Enrichment of euchromatic H3.3 increased chromatin accessibility and activated the expression of endogenous retrovirus elements, a phenomenon known as viral mimicry. However, cytosolic micronuclei and endogenous retroviruses are recognized as ectopic elements by the stimulator of interferon genes and dsRNA viral sensing pathways, respectively. As a result, the knockout of CAF-1 activated inflammatory response and antitumor immune surveillance and thereby significantly enhanced the anticancer effect of immune checkpoint inhibitors in HCC., Conclusions: Our findings suggest that CAF-1 is essential for HCC development; targeting CAF-1 may awaken the anticancer immune response and may work cooperatively with immune checkpoint inhibitor treatment in cancer therapy., (Copyright © 2023 American Association for the Study of Liver Diseases.)

The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer (GC). As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. Here, we identified a vital role of FOXP4 in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired GC spheroid formation and reduced stemness marker expression, while FOXP4 upregulation potentiated cancer cell stemness. RNA-seq analysis revealed SOX12 as downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small molecule screen identified 42-(2-Tetrazolyl)rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed GC tumor growth and enhanced the efficacy of 5-FU chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in GC regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for GC.

Mindfulness witnessed a substantial popularity surge in the past decade, especially as digitally self-administered interventions became available at relatively low costs. Yet, it is uncertain whether they effectively help reduce stress. In a preregistered (OSF https://doi.org/10.17605/OSF.IO/UF4JZ ; retrospective registration at ClinicalTrials.gov NCT06308744 ) multi-site study (n sites  = 37, n participants  = 2,239, 70.4% women, M age  = 22.4, s.d. age  = 10.1, all fluent English speakers), we experimentally tested whether four single, standalone mindfulness exercises effectively reduced stress, using Bayesian mixed-effects models. All exercises proved to be more efficacious than the active control. We observed a mean difference of 0.27 (d = -0.56; 95% confidence interval, -0.43 to -0.69) between the control condition (M = 1.95, s.d. = 0.50) and the condition with the largest stress reduction (body scan: M = 1.68, s.d. = 0.46). Our findings suggest that mindfulness may be beneficial for reducing self-reported short-term stress for English speakers from higher-income countries., (© 2024. The Author(s).)

Bacteria such as the oral microbiome member Peptostreptococcus anaerobius can exacerbate colorectal cancer (CRC) development. Little is known regarding whether these immunomodulatory bacteria also affect antitumour immune checkpoint blockade therapy. Here we show that administration of P. anaerobius abolished the efficacy of anti-PD1 therapy in mouse models of CRC. P. anaerobius both induced intratumoral myeloid-derived suppressor cells (MDSCs) and stimulated their immunosuppressive activities to impair effective T cell responses. Mechanistically, P. anaerobius administration activated integrin α 2 β 1 -NF-κB signalling in CRC cells to induce secretion of CXCL1 and recruit CXCR2 + MDSCs into tumours. The bacterium also directly activated immunosuppressive activity of intratumoral MDSCs by secreting lytC&#95;22, a protein that bound to the Slamf4 receptor on MDSCs and promoted ARG1 and iNOS expression. Finally, therapeutic targeting of either integrin α 2 β 1 or the Slamf4 receptor were revealed as promising strategies to overcome P. anaerobius-mediated resistance to anti-PD1 therapy in CRC., (© 2024. The Author(s).)

Objective: Squalene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour immune microenvironment in MASH-HCC remains unclear., Design: We established hepatocyte-specific Sqle transgenic (tg) and knockout mice, which were subjected to a choline-deficient high-fat diet plus diethylnitrosamine to induce MASH-HCC. SQLE function was also determined in orthotopic and humanised mice. Immune landscape alterations of MASH-HCC mediated by SQLE were profiled by single-cell RNA sequencing and flow cytometry., Results: Hepatocyte-specific Sqle tg mice exhibited a marked increase in MASH-HCC burden compared with wild-type littermates, together with decreased tumour-infiltrating functional IFN-γ + and Granzyme B + CD8 + T cells while enriching Arg-1 + myeloid-derived suppressor cells (MDSCs). Conversely, hepatocyte-specific Sqle knockout suppressed tumour growth with increased cytotoxic CD8 + T cells and reduced Arg-1 + MDSCs, inferring that SQLE promotes immunosuppression in MASH-HCC. Mechanistically, SQLE-driven cholesterol accumulation in tumour microenvironment underlies its effect on CD8 + T cells and MDSCs. SQLE and its metabolite, cholesterol, impaired CD8 + T cell activity by inducing mitochondrial dysfunction. Cholesterol depletion in vitro abolished the effect of SQLE-overexpressing MASH-HCC cell supernatant on CD8 + T cell suppression and MDSC activation, whereas cholesterol supplementation had contrasting functions on CD8 + T cells and MDSCs treated with SQLE-knockout supernatant. Targeting SQLE with genetic ablation or pharmacological inhibitor, terbinafine, rescued the efficacy of anti-PD-1 treatment in MASH-HCC models., Conclusion: SQLE induces an impaired antitumour response in MASH-HCC via attenuating CD8 + T cell function and augmenting immunosuppressive MDSCs. SQLE is a promising target in boosting anti-PD-1 immunotherapy for MASH-HCC., Competing Interests: Competing interests: None declared., (© 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.)

The landscape of the intratumoral microbiome in tumor metastases is largely unchartered. In this issue of Cell, Voest et al. profiled the tumor metastasis-associated microbiome in a pancancer cohort of 4,160 biopsies from 26 cancer types. This dataset offers a useful resource for understanding the role of the microbiome in metastatic cancers., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The present study aimed to investigate the effect of a blatant activation of age-based stereotype threats (ABST) on time-based prospective memory (TBPM) in older adults. A sample of 74 adults from Hong Kong was randomly assigned to one of the two experimental conditions: the stereotyped condition ( n = 36) or the neutral condition ( n = 38). Participants were asked to read fictitious news reports related to dementia (stereotyped condition) or the importance of English oral skills (neutral condition). After, all participants performed a TBPM task using the Chinese lexical decision task as an ongoing task block. The results indicate a main effect of ABST on TBPM accuracy. Specifically, older adults under a blatant activation of ABST demonstrated lower TBPM accuracy ( p < 0.05, ηp 2 = 0.08). Further analyses based on age groups demonstrated that TBPM accuracy was only impaired in older participants (aged 70-80 years) ( p < 0.05, ηp 2 = 0.19). The study, for the first time, provides evidence that ABST can disrupt TBPM performance in older adults, especially when cues are blatantly activated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tsang, Chan, Lu and Wong.)

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites. In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells, we performed a comprehensive genome-scale CRISPR screening of cancer cells. We found that four molecules belonging to the butyrophilin (BTN) family, specifically BTN2A1, BTN3A1, BTN3A2, and BTN3A3, are critically important and play unique, nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells. The coordinated function of these BTN molecules was driven by synchronized gene expression, which was regulated by IFN-γ signaling and the RFX complex. Additionally, an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells. Through our research, we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells. Moreover, our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

There is a lack of research that proposes a complete and interoperable robotics experimental design method to improve students' learning outcomes. Therefore, this study proposes a student-oriented method based on the plan-do-check-act (PDCA) concept to design robotics experiments. The proposed method is based on our teaching experience and multiple practical experiences of allowing students to do hands-on experiments. It consists of eight steps, mainly including experimental goals, experimental activities, robot assembly, robot control, in-class evaluation criteria, and after-class report requirements. The after-class report requirements designed in the proposed method can help students improve their report-writing abilities. A wall-following robotics experiment designed using the PDCA method is proposed, and some students' learning outcomes and after-class reports in this experiment are presented to illustrate the effectiveness of the proposed method. This experiment also helps students to understand the fundamental application of multi-sensor fusion technology in designing an autonomous mobile robot. We can see that the proposed reference examples allow students to quickly assemble two-wheeled mobile robots with four different sensors and to design programs to control these assembled robots. In addition, the proposed in-class evaluation criteria stimulate students' creativity in assembling different wall-following robots or designing different programs to achieve this experiment. We present the learning outcomes of three stages of the wall-following robotics experiment. Three groups of 42, 37, and 44 students participated in the experiment in these three stages, respectively. The ratios of the time required for the robots designed by students to complete the wall-following experiment, less than that of the teaching example, are 3/42 = 7.14%, 26/37 = 70.27%, and 44/44 = 100%, respectively. From the comparison of learning outcomes in the three stages, it can be seen that the proposed PDCA-based design method can indeed improve students' learning outcomes and stimulate their active learning and creativity.

Background and Aims: NASH-HCC is inherently resistant to immune checkpoint blockade, but its tumor immune microenvironment is largely unknown., Approach and Results: We applied the imaging mass cytometry to construct a spatially resolved single-cell atlas from the formalin-fixed and paraffin-embedded tissue sections from patients with NASH-HCC, virus-HCC (HBV-HCC and HCV-HCC), and healthy donors. Based on 35 biomarkers, over 750,000 individual cells were categorized into 13 distinct cell types, together with the expression of key immune functional markers. Higher infiltration of T cells, myeloid-derived suppressor cell (MDSCs), and tumor-associated macrophages (TAMs) in HCC compared to controls. The distribution of immune cells in NASH-HCC is spatially heterogeneous, enriched at adjacent normal tissues and declined toward tumors. Cell-cell connections analysis revealed the interplay of MDSCs and TAMs with CD8 + T cells in NASH-HCC. In particular, exhausted programmed cell death 1 (PD-1 + )CD8 + T cells connected with programmed cell death-ligand 1 (PD-L1 + )/inducible T cell costimulator (ICOS + ) MDSCs and TAMs in NASH-HCC, but not in viral HCC. In contrast, CD4 + /CD8 + T cells with granzyme B positivity were reduced in NASH-HCC. Tumor cells expressed low PD-L1 and showed few connections with immune cells., Conclusions: Our work provides the first detailed spatial map of single-cell phenotypes and multicellular connections in NASH-HCC. We demonstrate that interactions between MDSCs and TAMs with effector T cells underlie immunosuppression in NASH-HCC and are an actionable target., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)