A LATS2 and ALKBH5 positive feedback loop supports their oncogenic roles.

N(6)-methyladenosine (m6A) critically regulates RNA dynamics in various biological processes. The m6A demethylase ALKBH5 promotes tumorigenesis of glioblastoma, while the intricate web that orchestrates its regulation remains enigmatic. Here, we discover that cell density affects ALKBH5 subcellular localization and m6A dynamics. Mechanistically, ALKBH5 is phosphorylated by the large tumor suppressor kinase 2 (LATS2), preventing its nuclear export and enhancing protein stability. Furthermore, phosphorylated ALKBH5 reciprocally erases m6A from LATS2 mRNA, thereby stabilizing this transcript. Unexpectedly, LATS2 depletion suppresses glioblastoma stem cell self-renewal independent of yes-associated protein activation. Additionally, deficiency in either LATS2 or ALKBH5 phosphorylation impedes tumor progression in mouse xenograft models. Moreover, high levels of LATS2 expression and ALKBH5 phosphorylation are associated with tumor malignancy in patients with gliomas. Collectively, our study unveils an oncogenic positive feedback loop between LATS2 and ALKBH5, revealing a non-canonical branch of the Hippo pathway for RNA processing and suggesting potential anti-cancer interventions.

The Modified Neo-Bioscore System for Staging Breast Cancer Treated with Neoadjuvant Therapy Based on Prognostic Significance of HER2-Low Expression.

Background: Recently, the classification of HER2 status evolves from binary to ternary, and HER2-low expression may exhibit prognostic significance. We aimed to investigate whether HER2-low tumor is distinct from HER2-zero or HER2-positive tumors, and then to develop a modified staging system (mNeo-Bioscore) that incorporates HER2-low status into Neo-Bioscore. Patients and Methods: This cohort study was conducted using data from the prospective database on breast cancer patients between January 2014 and February 2019. Results: Among 259 patients enrolled in the study, the HER2-low tumor exhibited significantly lower histological grade, pathological staging and Ki-67 level than the other two groups. HER2-low patients and HER2-positive patients receiving concurrent HER2-directed therapy may have similar LRFS (p = 0.531) and OS (p = 0.853), while HER2-zero peers may have significantly worse LRFS (p = 0.006) and OS (p = 0.017). In particular, a similar trend was also found in the patients without pathological complete response after surgery. Incorporation of HER2-low status made improvement in fit: 5-year OS rate estimates ranged from 33.33% to 100% for mNeo-Bioscore vs 61.36% to 100% for Neo-Bioscore. Conclusions: This study demonstrated that HER2-low tumor may exhibit prognostic significance. The innovative mNeo-Bioscore, based on a new classification of HER2 status, may serve as a prognostic staging system superior to Neo-Bioscore.

Nuclear translocation of metabolic enzyme PKM2 participates in high glucose-promoted HCC metastasis by strengthening immunosuppressive environment.

Although some cohort studies have indicated a close association between diabetes and HCC, the underlying mechanism about the contribution of diabetes to HCC progression remains largely unknown. In the study, we applied a novel HCC model in SD rat with diabetes and a series of high glucose-stimulated cell experiments to explore the effect of a high glucose environment on HCC metastasis and its relevant mechanism. Our results uncovered a novel regulatory mechanism by which nuclear translocation of metabolic enzyme PKM2 mediated high glucose-promoted HCC metastasis. Specifically, high glucose-increased PKM2 nuclear translocation downregulates chemerin expression through the redox protein TRX1, and then strengthens immunosuppressive environment to promote HCC metastasis. To the best of our knowledge, this is the first report to elucidate the great contribution of a high glucose environment to HCC metastasis from a new perspective of enhancing the immunosuppressive microenvironment. Simultaneously, this work also highlights a previously unidentified non-metabolic role of PKM2 and opens a novel avenue for cross research and intervention for individuals with HCC and comorbid diabetes.

Single-cell RNA sequencing reveals immune cell dysfunction in the peripheral blood of patients with highly aggressive gastric cancer.

Highly aggressive gastric cancer (HAGC) is a gastric cancer characterized by bone marrow metastasis and disseminated intravascular coagulation (DIC). Information about the disease is limited. Here we employed single-cell RNA sequencing to investigate peripheral blood mononuclear cells (PBMCs), aiming to unravel the immune response of patients toward HAGC. PBMCs from seven HAGC patients, six normal advanced gastric cancer (NAGC) patients, and five healthy individuals were analysed by single-cell RNA sequencing. The expression of genes of interest was validated by bulk RNA-sequencing and ELISA. We found a massive expansion of neutrophils in PBMCs of HAGC. These neutrophils are activated, but immature. Besides, mononuclear phagocytes exhibited an M2-like signature and T cells were suppressed and reduced in number. Analysis of cell-cell crosstalk revealed that several signalling pathways involved in neutrophil to T-cell suppression including APP-CD74, MIF-(CD74+CXCR2), and MIF-(CD74+CD44) pathways were increased in HAGC. NETosis-associated genes S100A8 and S100A9 as well as VEGF, PDGF, FGF, and NOTCH signalling that contribute to DIC development were upregulated in HAGC too. This study reveals significant changes in the distribution and interactions of the PBMC subsets and provides valuable insight into the immune response in patients with HAGC. S100A8 and S100A9 are highly expressed in HAGC neutrophils, suggesting their potential to be used as novel diagnostic and therapeutic targets for HAGC.

Monitoring SF6 Gas Leakage Based on a Customized Binocular System.

Sulfur hexafluoride (SF6) gas is extensively utilized as an insulating and arc-quenching medium in the circuit breakers and isolating switches of electrical equipment. It effectively isolates the circuits from the atmosphere and promptly extinguishes arcs. Therefore, the issue of SF6 gas leakage poses a significant threat to the related application fields, and the detection of SF6 gas leakage becomes extremely important. Infrared imaging detection offers advantages including non-contact, high precision, and visualization. However, most existing infrared detection systems are equipped with only one filter to detect SF6 gas. The images captured contain background noise and system noise, making these systems vulnerable to interference from such noises. To address these issues, we propose a method for monitoring SF6 gas leakage based on a customized binocular imaging (CBI) system. The CBI system has two filters, greatly reducing the interference of system noise and background noise. The first filter features the absorption resonant peak of SF6 gas. The second filter is used to record background noise and system noise. One aspect to note is that, in order to avoid the interference of other gases, the central wavelength of this second filter should keep away from the absorption resonant peaks of those gases. Accordingly, the central wavelengths of our customized filters were determined as 10,630 nm and 8370 nm, respectively. Then, two cameras of the same type were separately assembled with a customized filter, and the CBI prototype was accomplished. Finally, we utilized the difference method using two infrared images captured by the CBI system, to monitor the SF6 gas leakage. The results demonstrate that our developed system achieves a high accuracy of over 99.8% in detecting SF6 gas. Furthermore, the CBI system supports a plug-and-play customization to detect various gases for different scenarios.

BST2 promotes gastric cancer metastasis under the regulation of HOXD9 and PABPC1.

Gastric cancer (GC) constitutes substantial cancer mortality worldwide. Several cancer types aberrantly express bone marrow stromal cell antigen 2 (BST2), yet its functional and underlying mechanisms in GC progression remain unknown. In our study, RNA sequencing data revealed that BST2 was transcriptionally activated by homeobox D9 (HOXD9). BST2 was significantly upregulated in GC tissues and promoted epithelial-mesenchymal transition and metastasis of GC. BST2 knockdown reversed HOXD9's oncogenic effect on GC metastasis. Moreover, BST2 messenger RNA stability could be enhanced by poly(A) binding protein cytoplasmic 1 (PABPC1) through the interaction between BST2 3'-UTR and PABPC1 in GC cells. PABPC1 promoted GC metastasis, which BST2 silencing attenuated in vitro and in vivo. In addition, positive correlations among HOXD9, BST2, and PABPC1 were established in clinical samples. Taken together, increased expression of BST2 induced by HOXD9 synergizing with PABPC1 promoted GC cell migration and invasion capacity.

Ultra-Processed Food Consumption and Mortality: Three Cohort Studies in the United States and United Kingdom.

INTRODUCTION: Given the increase in ultra-processed food (UPF) consumption, their potential health effects have aroused concern. Whether UPF consumption is associated with cancer and cardiovascular disease mortality is debatable. This study evaluates the association of UPF consumption with mortality. METHODS: A total of 108,714 U.S. adults from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (1993-2001), 208,051 UK adults from UK Biobank (2006-2010), and 41,070 U.S. adults from National Health and Nutrition Examination Survey (1999-2018) were included. Dietary data were collected by dietary questionnaire and classified using the NOVA classification. UPF consumption was expressed as the weight proportion of UPFs in total foods consumed. Cox proportional hazard models were used to calculate hazard ratios and 95% CIs. Mediation analysis was used to evaluate whether multiple metabolic pathways mediated the associations in UK Biobank. Analyses were performed in 2022-2023. RESULTS: Combined analyses of the three cohorts showed that those with the highest quartile of UPF consumption had higher risks of all-cause mortality (hazard ratio, 1.16; 95% CI, 1.11-1.20) and cardiovascular disease mortality (hazard ratio, 1.17; 95% CI, 1.06-1.28) compared to the lowest quartile of UPF consumption. UPF consumption was not associated with cancer mortality risk. Biomarkers of liver function have the greatest mediating effects on all-cause mortality (20.3%), and biomarkers of inflammation have the greatest mediating effects on cardiovascular disease mortality (29.2%). CONCLUSIONS: Higher UPF consumption was associated with increased all-cause and cardiovascular disease mortality risk, with multiple metabolic pathways playing mediating roles.

A synergistic regulation works in matrix stiffness-driven invadopodia formation in HCC.

Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells. However, whether and how increased matrix stiffness regulates the formation of invadopodia in HCC cells remain largely unknown. In the study, we developed different experimental systems in vitro and in vivo to explore the effects of matrix stiffness on the formation of invadopodia and its relevant molecular mechanism. Our results demonstrated that increased matrix stiffness remarkably augmented the migration and invasion abilities of HCC cells, upregulated the expressions of invadopodia-associated genes and enhanced the number of invadopodia. Two regulatory pathways contribute to matrix stiffness-driven invadopodia formation together in HCC cells, including direct triggering invadopodia formation through activating integrin ß1 or Piezo1/ FAK/Src/Arg/cortactin pathway, and indirect stimulating invadopodia formation through improving EGF production to activate EGFR/Src/Arg/cortactin pathway. Src was identified as the common hub molecule of two synergistic regulatory pathways. Simultaneously, activation of integrin ß1/RhoA/ROCK1/MLC2 and Piezo1/Ca2+/MLCK/MLC2 pathways mediate matrix stiffness-reinforced cell migration. This study uncovers a new mechanism by which mechanosensory pathway and biochemical signal pathway synergistically regulate the formation of invadopodia in HCC cells.

Time trends of 16 modifiable risk factors on the burden of major cancers among the Chinese population.

The cancer burden in China is increasing. We aimed to assess the time trends in the prevalence of 16 modifiable risk factors involved in lifestyle, diet, infection, and air pollution between 1997 and 2025 based on the China Health and Nutrition Survey, the Global Burden of Disease website, and publically available studies. The population attributable fraction (PAF) and its 95% uncertainty interval (UI) from 2007 to 2035 were calculated to quantify the attributable cancer burden in major 12 anatomic sites using the comparative risk assessment method, considering a 10-year lag effect. As a result, 1,559,476 cancer cases (PAF = 54.1%, 95% UI: 36.8%-65.8%) from the 12 anatomic sites were attributable to these modifiable risk factors in 2007, with lung, liver, and gastric cancer raging the top three. It was predicted that by 2035, the attributable cancer cases would reach 1,680,098 (PAF = 44.2%, 95% UI: 29.1%-55.5%), with the top three of lung, liver, and colorectal cancer. Smoking, physical inactivity, insufficient fruit consumption, HBV infection, and Helicobacter pylori infection were the most attributable risk factors in 2007, contributing to 480,352, 233,684, 215,009, 214,455, and 187,305 associated cancer cases, respectively. In 2035, the leading factors for cancer would be smoking, physical inactivity, insufficient fruit intake, HPV infection, and HBV infection, resulting in 427,445, 424,327, 185,144, 156,535, and 154,368 cancer cases, respectively. Intervention strategies should be swiftly established and dynamically altered in response to risk factors like smoking, physical inactivity, poor fruit intake, and infectious factors that may cause a high cancer burden in the Chinese population.

Magnetic resonance imaging radiomics-based prediction of clinically significant prostate cancer in equivocal PI-RADS 3 lesions in the transitional zone.

Purpose: This bi-institutional study aimed to establish a robust model for predicting clinically significant prostate cancer (csPCa) (pathological grade group ≥ 2) in PI-RADS 3 lesions in the transition zone by comparing the performance of combination models. Materials and methods: This study included 243 consecutive men who underwent 3-Tesla magnetic resonance imaging (MRI) and ultrasound-guided transrectal biopsy from January 2020 and April 2022 which is divided into a training cohort of 170 patients and a separate testing cohort of 73 patients. T2WI and DWI images were manually segmented for PI-RADS 3 lesions for the mean ADC and radiomic analysis. Predictive clinical factors were identified using both univariate and multivariate logistic models. The least absolute shrinkage and selection operator (LASSO) regression models were deployed for feature selection and for constructing radiomic signatures. We developed nine models utilizing clinical factors, radiological features, and radiomics, leveraging logistic and XGboost methods. The performances of these models was subsequently compared using Receiver Operating Characteristic (ROC) analysis and the Delong test. Results: Out of the 243 participants with a median age of 70 years, 30 were diagnosed with csPCa, leaving 213 without a csPCa diagnosis. Prostate-specific antigen density (PSAD) stood out as the only significant clinical factor (odds ratio [OR], 1.068; 95% confidence interval [CI], 1.029-1.115), discovered through the univariate and multivariate logistic models. Seven radiomic features correlated with csPCa prediction. Notably, the XGboost model outperformed eight other models (AUC of the training cohort: 0.949, and validation cohort: 0.913). However, it did not surpass the PSAD+MADC model (P > 0.05) in the training and testing cohorts (AUC, 0.949 vs. 0.888 and 0.913 vs. 0.854, respectively). Conclusion: The machine learning XGboost model presented the best performance in predicting csPCa in PI-RADS 3 lesions within the transitional zone. However, the addition of radiomic classifiers did not display any significant enhancement over the compound model of clinical and radiological findings. The most exemplary and generalized option for quantitative prostate evaluation was Mean ADC+PSAD.

Tree Frog-Derived Cathelicidin Protects Mice against Bacterial Infection through Its Antimicrobial and Anti-Inflammatory Activities and Regulatory Effect on Phagocytes.

Due to excessive use or abuse in the food industry, agriculture, and medicine, many pathogens are developing resistance against conventional antibiotics. Antimicrobial peptides (AMPs) hold promise as effective therapeutic options for the treatment of bacterial infections. Herein, a novel cathelicidin antimicrobial peptide (Zs-CATH) was identified from the tree frog Zhangixalus smaragdinus. Zs-CATH mainly adopted an amphipathic ß-sheet structure in a membrane-mimetic environment. It showed broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria in vitro and significantly protected mice from lethal infections induced by Gram-negative bacteria Escherichia coli ATCC 25922 or Gram-positive bacteria Staphylococcus aureus ATCC 25923 in vivo. In addition, Zs-CATH exerted a strong anti-inflammatory effect by neutralizing lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and promoting macrophage M2 polarization, thus inhibiting the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1ß) and enhancing the production of M2 macrophage markers IL-10, IL-4, and CD206. The MAPK and NF-κB inflammatory signaling pathways and transcriptional activator 6 (STAT6) were involved in this effect. In mice, Zs-CATH rapidly recruited neutrophils and monocytes/macrophages to the abdominal cavity but not T and B lymphocytes. Zs-CATH did not exhibit a direct chemoattractant effect on phagocytes but significantly promoted phagocyte migration in the presence of macrophages. Zs-CATH stimulated macrophages to secrete chemokines CXCL1, CXCL2, and CCL2, which mediated the recruitment of phagocytes. Furthermore, Zs-CATH promoted the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), which are oxygen-dependent and oxygen-independent mechanisms of the microbicidal activity of neutrophils, respectively. Zs-CATH exhibited no toxic side effects on mammalian cells and mice. These findings show that in addition to direct antibacterial activity, Zs-CATH also possesses the ability to modulate immune and inflammatory processes during bacterial infection, showing potential for development as anti-infective and/or anti-inflammatory agents.

Control of the antitumour activity and specificity of CAR T cells via organic adapters covalently tethering the CAR to tumour cells.

On-target off-tumour toxicity limits the anticancer applicability of chimaeric antigen receptor (CAR) T cells. Here we show that the tumour-targeting specificity and activity of T cells with a CAR consisting of an antibody with a lysine residue that catalytically forms a reversible covalent bond with a 1,3-diketone hapten can be regulated by the concentration of a small-molecule adapter. This adapter selectively binds to the hapten and to a chosen tumour antigen via a small-molecule binder identified via a DNA-encoded library. The adapter therefore controls the formation of a covalent bond between the catalytic antibody and the hapten, as well as the tethering of the CAR T cells to the tumour cells, and hence the cytotoxicity and specificity of the cytotoxic T cells, as we show in vitro and in mice with prostate cancer xenografts. Such small-molecule switches of T-cell cytotoxicity and specificity via an antigen-independent 'universal' CAR may enhance the control and safety profile of CAR-based cellular immunotherapies.

Potential impact of time trend of whole grain intake on burden of major cancers in China.

Numerous studies have revealed associations between high intake of whole grains and reduced risk of various cancers. Yet, in recent decades, the traditional Chinese diets have been challenged by reduction in whole grains and increase in refined grains. To assess the impact of this dietary transition on cancer prevention, we analyzed the time trend of whole grain intake using nationally representative sampling data of over 15 thousand individuals from the China Health and Nutrition Survey. We applied the comparative risk assessment method to estimate the population attributable fraction of cancers due to insufficient whole grain intake from 1997 to 2011 and projected the trend of whole grain intake and the associated burden of cancers to 2035. We found a significant decrease of approximately 59% of whole grain intake in the Chinese population from 1997 to 2011. Compared with 1997, insufficient intake of whole grains was responsible for 9940 more cases of breast cancer, 12,903 more cases of colorectal cancer and 434 more cases of pancreatic cancer in 2011. Our projections suggest that if every Chinese would consume 125 g whole grain per day as recommended by the latest Chinese Dietary Guidelines, 0.63% bladder cancer, 8.98% breast cancer, 15.85% colorectal cancer, 3.86% esophageal cancer, 2.52% liver cancer and 2.22% pancreatic cancer (totaling 186,659 incident cases) could theoretically be averted by 2035. Even if everyone maintained the 2011 whole grain intake level, an estimated 8.38% of cancer events could still be prevented by 2035.

Comparison of the gut microbiota and untargeted gut tissue metabolome of Chinese mitten crabs (Eriocheir sinensis) with different shell colors.

Introduction: The Chinese mitten crab (Eriocheir sinensis) is a highly valued freshwater crustacean in China. While the natural shell color of E. sinensis is greenish brown (GH), we found a variety with a brownish-orange shell color (RH). Although RH is more expensive, it exhibits a lower molting frequency and growth rate compared with GH, which significantly reduces its yield and hinders large-scale farming. The growth and development of animals are closely related to their gut microbiota and gut tissue metabolic profiles. Methods: In this study, we compared the gut microbiome communities and metabolic profiles of juvenile RH and GH crabs using 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS), respectively. Results: Our findings indicated that the intestinal microbial composition and metabolic characteristics of E. sinensis differed significantly between RH and GH. At the operational taxonomic unit (OTU) level, the α-diversity of the gut microbiota did not differ significantly between RH and GH, while the ß-diversity of the RH gut microbiota was higher than that of the GH gut microbiota. At the species level, the richness of unclassified_c_Alphaproteobacteria was significantly higher in the GH group, while the RH group had a significantly higher richness of three low-abundance species, Flavobacteria bacterium BAL38, Paraburkholderia ferrariae, and uncultured_bacterium_g__Legionella. In the current study, 598 gut tissue metabolites were identified, and 159 metabolites were significantly different between GH and RH. The metabolite profile of RH was characteristic of a low level of most amino acids and lipid metabolites and a high level of several pigments compared with that of GH. These metabolites were enriched in 102 KEGG pathways. Four pathways, including (1) Central carbon metabolism in cancer, (2) protein digestion and absorption, (3) alanine, aspartate and glutamate metabolism, and (4) aminoacyl-tRNA biosynthesis, were significantly enriched. The correlation analysis between metabolites and microbiotas indicated that most key differential metabolites were positively correlated with the abundance of Shewanella_sp_MR-7. Discussion: This research provided a greater understanding of the physiological conditions of E. sinensis varieties with different shell colors by comparing the gut microbiota and gut tissue metabolome.

CAPG interference induces apoptosis and ferroptosis in colorectal cancer cells through the P53 pathway.

PURPOSE: Given the high incidence and mortality rates of colorectal cancer (CRC) and the inadequacy of existing treatments for many patients, this study aimed to explore the potential of Capping Actin Protein (CAPG), a protein involved in actin-related movements, as a novel therapeutic target for CRC. METHODS: Bioinformatic analysis of gene expression was conducted using the UALCAN website. Cell proliferation was measured using the CCK-8 kit. Cell cycle, apoptosis, and ferroptosis were analyzed using flow cytometry. Tumorigenesis was evaluated by the subcutaneous inoculation of CRC cells into BALB/c nude female mice. Differentially expressed genes and signaling pathways were identified using RNA sequencing. RESULTS: CAPG was significantly overexpressed in human CRC tissues and its upregulation was correlated with poor overall survival. CAPG knockdown led to notable inhibition of CRC cells in vitro and in vivo. Interference with CAPG blocked the cell cycle at the G1 phase and triggered apoptosis and ferroptosis by upregulating the P53 pathway in CRC cells. CONCLUSION: CRC patients with higher CAPG levels have a poorer prognosis. CAPG inhibits apoptosis and ferroptosis, while promoting CRC cell proliferation by repressing the P53 pathway. Our study suggests that CAPG may be a potential therapeutic target for CRC prognosis and treatment.

Factors associated with hospitalization times and length of stay in patients with bipolar disorder.

Aim: Appraise the clinical features and influencing factors of the hospitalization times and length of stay in bipolar disorder (BD) patients. Methods: This is a multicenter, observational, cohort study of patients diagnosed of type I or type II bipolar disorder. Five hundred twenty outpatients in seven hospitals from six cities in China were recruited from February 2013 to June 2014 and followed up using a continuous sampling pattern. The research included a retrospective period of 12 months and the prospective period of 9 months. The demographic and clinical features of the patients were collected. The influencing factors that could affect the length of stay (number of days spent in the hospital in the prospective period) were analyzed by poisson's regression and the hospitalization times (times of hospitalization in the prospective and retrospective period) was analyzed by general linear model. The selected variables included gender, age, years of education, occupational status, residence status, family history of mental disease, comorbid substance abuse, comorbid anxiety disorder, times of suicide (total suicide times that occurred in the retrospective and prospective period), polarity of the first mood episode, and BD type(I/II). Results: Poisson's regression analysis showed that suicide times [Incidence Rate Ratio (IRR) = 1.20, p < 0.001], use of antipsychotic (IRR = 0.62, p = 0.011), and use of antidepressant (IRR = 0.56, p < 0.001) were correlated to more hospitalization times. Linear regression analysis showed that BD type II (ß = 0.28, p = 0.005) and unemployment (ß = 0.16, p = 0.039) which might mean longer duration of depression and poor function were correlated to longer length of stay. However, patients who experienced more suicide times (ß = -0.21, p = 0.007) tended to have a shorter length of stay. Conclusion: Overall, better management of the depressive episode and functional rehabilitation may help to reduce the length of stay. BD patients with more hospitalization times were characterized by higher risk of suicide and complex polypharmacy. Patients at high risk of suicide tended to have inadequate therapy and poor compliance, which should be assessed and treated adequately during hospitalization. Clinical trial registration: www.ClinicalTrials.gov, Identifier: NCT01770704.

Non-canonical role of UCKL1 on ferroptosis defence in colorectal cancer.

BACKGROUND: Pyrimidine nucleotides fuel the growth of colorectal cancer (CRC), making their associated proteins potential targets for cancer intervention. Uridine-Cytidine Kinase Like-1(UCKL1) is an enzyme involved in the pyrimidine salvage pathway. It is highly expressed in multiple cancers. But the function and underlying mechanism of UCKL1 in CRC are yet to study. METHODS: Large-scale genomic analysis was performed to search for potential CRC players related to pyrimidine metabolism. The function of UCKL1 in CRC were examined by RNA interference coupled with in vitro and in vivo assays. GSH/GSSG assay, NADP+ assay, ROS, and Lipid peroxidation assays were performed to check the function of UCKL1 in ferroptosis. Metabolomics analyses, RNA sequencing, western blotting, and rescue assays were done to reveal the underlying mechanisms of UCKL1. Xenograft mouse model was used to examine the therapeutic potential of UCKL1 as a target in combination with other ferroptosis inducers. FINDINGS: UCKL1 was identified to repress ferroptosis in CRC cells. It was highly expressed in CRC. It regulated CRC cells proliferation and migration. Downregulation of UCKL1 led to enhanced tumour lipid peroxidation. Intriguingly, UCKL1 reduction-mediated ferroptosis was not related to its role in catalyzing uridine monophosphate (UMP) and cytidine monophosphate (CMP) synthesis. Instead, UCKL1 stabilized Nrf2, which in turn promoted the expression of SLC7A11, a classical repressor of ferroptosis. Moreover, downregulation of UCKL1 sensitized CRC cells to GPX4 inhibitors in vitro and in vivo. INTERPRETATION: Our study demonstrates that UCKL1 plays a non-canonical role in repressing ferroptosis through a UCKL1-Nrf2-SLC7A11 axis in CRC cells. Combinatorial strategy in targeting ferroptosis by depletion of UCKL1 and application of GPX4 inhibitors may serve as a new effective method for CRC treatment. FUNDING: This study was supported in part by fund from National Natural Science Foundation of China (Grant No. 31970674 to PY), by the Basic and Applied Basic Research Program of Guangdong Province (Grant No. 2023A1515030245 to KL), by the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), and by National Key Clinical Discipline.

Chloroquine Inhibition of Autophagy Enhanced the Anticancer Effects of Listeria monocytogenes in Melanoma.

Listeria monocytogenes has been shown to exhibit antitumor effects. However, the mechanism remains unclear. Autophagy is a cellular catabolic process that mediates the degradation of unfolded proteins and damaged organelles in the cytosol, which is a double-edged sword in tumorigenesis and treatment outcome. Tumor cells display lower levels of basal autophagic activity than normal cells. This study examined the role and molecular mechanism of autophagy in the antitumor effects induced by LM, as well as the combined antitumor effect of LM and the autophagy inhibitor chloroquine (CQ). We investigated LM-induced autophagy in B16F10 melanoma cells by real-time PCR, immunofluorescence, Western blotting, and transmission electron microscopy and found that autophagic markers were increased following the infection of tumor cells with LM. The autophagy pathway in B16F10 cells was blocked with the pharmacological autophagy inhibitor chloroquine, which led to a significant increase in intracellular bacterial multiplication in tumor cells. The combination of CQ and LM enhanced LM-mediated cancer cell death and apoptosis compared with LM infection alone. Furthermore, the combination of LM and CQ significantly inhibited tumor growth and prolonged the survival time of mice in vivo, which was associated with the increased colonization and accumulation of LM and induced more cell apoptosis in primary tumors. The data indicated that the inhibition of autophagy by CQ enhanced LM-mediated antitumor activity in vitro and in vivo and provided a novel strategy to improving the anticancer efficacy of bacterial treatment.

Porous Framework Materials for Bioimaging and Cancer Therapy.

Cancer remains one of the most pressing diseases in the world. Traditional treatments, including surgery, chemotherapy, and radiotherapy still show certain limitations. Recently, numerous cancer treatments have been proposed in combination with novel materials, such as photothermal therapy, chemodynamic therapy, immunotherapy, and a combination of therapeutic approaches. These new methods have shown significant advantages in reducing side effects and synergistically enhancing anti-cancer efficacy. In addition to the above approaches, early diagnosis and in situ monitoring of lesion areas are also important for reducing side effects and improving the success rate of cancer therapy. This depends on the decent use of bioimaging technology. In this review, we mainly summarize the recent advances in porous framework materials for bioimaging and cancer therapy. In addition, we present future challenges relating to bioimaging and cancer therapy based on porous framework materials.