KLF12 interacts with TRIM27 to affect cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma by regulating L1CAM expression.

Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment.

Integration of multiomics features for blood-based early detection of colorectal cancer.

BACKGROUND: Early detection of colorectal cancer (CRC) significantly enhances patient outcomes. Conventional CRC screening tools, like endoscopy and stool-based tests, have constraints due to their invasiveness or suboptimal patient adherence. Recently, liquid biopsy employing plasma cell-free DNA (cfDNA) has emerged as a potential noninvasive screening technique for various malignancies. METHODS: In this research, we harnessed the Mutation Capsule Plus (MCP) technology to profile an array of genomic characteristics from cfDNA procured from a single blood draw. This profiling encompassed DNA methylation, the 5' end motif, copy number variation (CNV), and genetic mutations. An integrated model built upon selected multiomics biomarkers was trained using a cohort of 93 CRC patients and 96 healthy controls. RESULTS: This model was subsequently validated in another cohort comprising 89 CRC patients and 95 healthy controls. Remarkably, the model achieved an area under the curve (AUC) of 0.981 (95% confidence interval (CI), 0.965-0.998) in the validation set, boasting a sensitivity of 92.1% (95% CI, 84.5%-96.8%) and a specificity of 94.7% (95% CI, 88.1%-98.3%). These numbers surpassed the performance of any single genomic feature. Importantly, the sensitivities reached 80% for stage I, 89.2% for stage II, and were 100% for stages III and IV. CONCLUSION: Our findings underscore the clinical potential of our multiomics liquid biopsy test, indicating its prospective role as a noninvasive method for early-stage CRC detection. This multiomics approach holds promise for further refinement and broader clinical application.

Multifunctional Heterostructured Fe3O4-FeTe@MCM Electrocatalyst Enabling High-Performance Practical Lithium-Sulfur Batteries Via Built-in Electric Field.

The development of capable of simultaneously modulating the sluggish electrochemical kinetics, shuttle effect, and lithium dendrite growth is a promising strategy for the commercialization of lithium-sulfur batteries. Consequently, an elaborate preparation method is employed to create a host material consisting of multi-channel carbon microspheres (MCM) containing highly dispersed heterostructure Fe3O4-FeTe nanoparticles. The Fe3O4-FeTe@MCM exhibits a spontaneous built-in electric field (BIEF) and possesses both lithophilic and sulfophilic sites, rendering it an appropriate host material for both positive and negative electrodes. Experimental and theoretical results reveal that the existence of spontaneous BIEF leads to interfacial charge redistribution, resulting in moderate polysulfide adsorption which facilitates the transfer of polysulfides and diffusion of electrons at heterogeneous interfaces. Furthermore, the reduced conversion energy barriers enhanced the catalytic activity of Fe3O4-FeTe@MCM for expediting the bidirectional sulfur conversion. Moreover, regulated Li deposition behavior is realized because of its high conductivity and remarkable lithiophilicity. Consequently, the battery exhibited long-term stability for 500 cycles with 0.06% capacity decay per cycle at 5 C, and a large areal capacity of 7.3 mAh cm-2 (sulfur loading: 9.73 mg cm-2) at 0.1 C. This study provides a novel strategy for the rational fabrication of heterostructure hosts for practical Li-S batteries.

Outcomes following KRASG12C inhibitor treatment in patients with KRASG12C-mutated solid tumors: A systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of FDA-approved KRASG12C inhibitors in patients with KRASG12C-mutated solid tumors. METHODS: We searched PubMed, EMBASE, Cochrane Library, and major international conferences for clinical trials published in English up to March 6, 2023. Clinical trials investigating sotorasib or adagrasib and reporting the clinical outcomes of the objective response rate (ORR), disease control rate (DCR), or incidence rate of grade ≥ 3 adverse events (AEs) were eligible. The primary endpoint was the ORR. Secondary endpoints included the DCR, incidence rate of grade ≥ 3 AEs, and odds ratio (OR) of the ORR between patients with or without co-mutation. The Random-effects model was applied for the outcomes of interest. RESULTS: 18 studies with 1224 patients were included in this meta-analysis. The pooled ORR, DCR, and incidence rate of grade ≥ 3 AEs were 31 % (95 % CI, 25-37 %), 86 % (95 % CI, 82-89 %), and 29 % (95 % CI, 23-36 %), respectively. KRASG12C-mutated NSCLC patients with a co-mutation of KEAP1 exhibited a worse ORR than those with wild-type KEAP1 (OR: 0.35, 95 % CI: 0.16-0.77). CONCLUSIONS: This study provided a comprehensive understanding of the efficacy and safety of KRASG12C inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRASG12C inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRASG12C inhibitor treatment.

High Rate and Low-Temperature Stable Lithium Metal Batteries Enabled by Lithiophilic 3D Cu-CuSn Porous Framework.

Lithium (Li) metal is regarded as the "Holy Grail" of anodes for high-energy rechargeable lithium batteries by virtue of its ultrahigh theoretical specific capacity and the lowest redox potential. However, the Li dendrite impedes the practical application of Li metal anodes. Herein, lithiophilic three-dimensional Cu-CuSn porous framework (3D Cu-CuSn) was fabricated by a vapor phase dealloying strategy via the difference in saturated vapor pressure between different metals and the Kirkendall effect. CuSn alloy sites were converted into LiSn alloy sites through the molten Li infusion method, and composite Li metal anodes (3D Cu-LiSn-Li) are achieved. Alloyed tin, as the bridge between the porous copper substrate and metallic Li, plays a critical role in optimizing Li nucleation and enhancing the fast lithium migration kinetics. This work demonstrates that lithiophilic binary copper alloys are an effective way to achieve room-temperature high rate performance and satisfied low-temperature cycling stability for Li metal batteries.

Squalene Epoxidase: Its Regulations and Links with Cancers.

Squalene epoxidase (SQLE) is a key enzyme in the mevalonate-cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate-cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers.

Transcriptome Sequencing Unveils a Molecular-Stratification-Predicting Prognosis of Sarcoma Associated with Lipid Metabolism.

Sarcomas are heterogeneous connective tissue malignancies that have been historically categorized into soft tissue and bone cancers. Although multimodal therapies are implemented, many sarcoma subtypes are still difficult to treat. Lipids play vital roles in cellular activities; however, ectopic levels of lipid metabolites have an impact on tumor recurrence, metastasis, and drug resistance. Thus, precision therapies targeting lipid metabolism in sarcoma need to be explored. In this study, we performed a comprehensive analysis of molecular stratification based on lipid metabolism-associated genes (LMAGs) using both public datasets and the data of patients in our cohort and constructed a novel prognostic model consisting of squalene epoxidase (SQLE) and tumor necrosis factor (TNF). We first integrated information on gene expression profile and survival outcomes to divide TCGA sarcoma patients into high- and low-risk subgroups and further revealed the prognosis value of the metabolic signature and immune infiltration of patients in both groups, thus proposing various therapeutic recommendations for sarcoma. We observed that the low-risk sarcoma patients in the TCGA-SARC cohort were characterized by high proportions of immune cells and increased expression of immune checkpoint genes. Subsequently, this lipid metabolic signature was validated in four external independent sarcoma datasets including the CHCAMS cohort. Notably, SQLE, a rate-limiting enzyme in cholesterol biosynthesis, was identified as a potential therapeutic target for sarcoma. Knockdown of SQLE substantially inhibited cell proliferation and colony formation while promoting the apoptosis of sarcoma cells. Terbinafine, an inhibitor of SQLE, displayed similar tumor suppression capacity in vitro. The prognostic predictive model and the potential drug target SQLE might serve as valuable hints for further in-depth biological, diagnostic, and therapeutic exploration of sarcoma.

Cuproptosis: mechanisms and links with cancers.

Cuproptosis was a copper-dependent and unique kind of cell death that was separate from existing other forms of cell death. The last decade has witnessed a considerable increase in investigations of programmed cell death, and whether copper induced cell death was an independent form of cell death has long been argued until mechanism of cuproptosis has been revealed. After that, increasing number of researchers attempted to identify the relationship between cuproptosis and the process of cancer. Thus, in this review, we systematically detailed the systemic and cellular metabolic processes of copper and the copper-related tumor signaling pathways. Moreover, we not only focus on the discovery process of cuproptosis and its mechanism, but also outline the association between cuproptosis and cancers. Finally, we further highlight the possible therapeutic direction of employing copper ion ionophores with cuproptosis-inducing functions in combination with small molecule drugs for targeted therapy to treat specific cancers.

Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies.

Interleukin-2 (IL-2) and its receptor (IL-2R) are essential in orchestrating immune responses. Their function and expression in the tumor microenvironment make them attractive targets for immunotherapy, leading to the development of IL-2/IL-2R-targeted therapeutic strategies. However, the dynamic interplay between IL-2/IL-2R and various immune cells and their dual roles in promoting immune activation and tolerance presents a complex landscape for clinical exploitation. This review discusses the pivotal roles of IL-2 and IL-2R in tumorigenesis, shedding light on their potential as diagnostic and prognostic markers and their therapeutic manipulation in cancer. It underlines the necessity to balance the anti-tumor activity with regulatory T-cell expansion and evaluates strategies such as dose optimization and selective targeting for enhanced therapeutic effectiveness. The article explores recent advancements in the field, including developing genetically engineered IL-2 variants, combining IL-2/IL-2R-targeted therapies with other cancer treatments, and the potential benefits of a multidimensional approach integrating molecular profiling, immunological analyses, and clinical data. The review concludes that a deeper understanding of IL-2/IL-2R interactions within the tumor microenvironment is crucial for realizing the full potential of IL-2-based therapies, heralding the promise of improved outcomes for cancer patients.

Efficacy of cell-free DNA methylation-based blood test for colorectal cancer screening in high-risk population: a prospective cohort study.

BACKGROUND: Although colonoscopy is the standard screening test for colorectal cancer (CRC), its use is limited by a poor compliance rate, the need for extensive bowel preparation, and the risk of complications. As an alternative, an FDA-approved stool-based DNA test, Cologuard, has demonstrated satisfactory detection performance for CRC, but its compliance rate remains suboptimal, primarily attributable to individuals' reluctance to provide stool samples. METHODS: We developed a noninvasive blood-based CRC test, ColonSecure, based on cell-free DNA containing cancer-specific CpG island methylation patterns. We initially screened publicly available datasets for differentially methylated CpG sites in CRC with prediction potential. Subsequently, we performed two sequential bisulfite-free methylation sequencing on blood samples obtained from CRC patients and non-cancer controls. Through rigorous evaluation of each marker and machine learning-assisted feature selection, we identified 149 hypermethylated markers from over 193,000 CpG sites. These markers were then utilized to construct the ColonSecure model, enabling accurate CRC detection. RESULTS: We validated the efficacy of our cell-free DNA methylation-based blood test for CRC screening with 3493 high-risk individuals identified from 114,136 urban residents. The ColonSecure test identified 89 out of 103 CRC patients diagnosed by the follow-up colonoscopy, outperforming CEA, CRP, and CA19-9 (with a sensitivity of 86.4% compared to 45.6%, 39.8%, and 25.2% for CEA, CRP, and CA19-9 respectively; an AUROC of 0.956 compared to an AUROC of < 0.77 for other methods). CONCLUSION: Our observations emphasize the potential of our multiple cfDNA methylation marker-based test for CRC screening in high-risk populations.