In-Depth Serum Proteomics Reveals the Trajectory of Hallmarks of Cancer in Hepatitis B Virus-Related Liver Diseases.

Hepatocellular carcinoma (HCC) is a prevalent cancer in China, with chronic hepatitis B (CHB) and liver cirrhosis (LC) being high-risk factors for developing HCC. Here, we determined the serum proteomes (762 proteins) of 125 healthy controls and Hepatitis B virus-infected CHB, LC, and HCC patients and constructed the first cancerous trajectory of liver diseases. The results not only reveal that the majority of altered biological processes were involved in the hallmarks of cancer (inflammation, metastasis, metabolism, vasculature, and coagulation) but also identify potential therapeutic targets in cancerous pathways (i.e., IL17 signaling pathway). Notably, the biomarker panels for detecting HCC in CHB and LC high-risk populations were further developed using machine learning in two cohorts comprised of 200 samples (discovery cohort = 125 and validation cohort = 75). The protein signatures significantly improved the area under the receiver operating characteristic curve of HCC (CHB discovery and validation cohort = 0.953 and 0.891, respectively; LC discovery and validation cohort = 0.966 and 0.818, respectively) compared to using the traditional biomarker, alpha-fetoprotein, alone. Finally, selected biomarkers were validated with parallel reaction monitoring mass spectrometry in an additional cohort (n = 120). Altogether, our results provide fundamental insights into the continuous changes of cancer biology processes in liver diseases and identify candidate protein targets for early detection and intervention.

An Innovative Approach for Removing Stripe Noise in Infrared Images.

The non-uniformity of infrared detectors' readout circuits can lead to stripe noise in infrared images, which affects their effective information and poses challenges for subsequent applications. Traditional denoising algorithms have limited effectiveness in maintaining effective information. This paper proposes a multi-level image decomposition method based on an improved LatLRR (MIDILatLRR). By utilizing the global low-rank structural characteristics of stripe noise, the noise and smooth information are decomposed into low-rank part images, and texture information is adaptively decomposed into several salient part images, thereby better preserving texture edge information in the image. Sparse terms are constructed according to the smoothness of the effective information in the final low-rank part of the image and the sparsity of the stripe noise direction. The modeling of stripe noise is achieved using multi-sparse constraint representation (MSCR), and the Alternating Direction Method of Multipliers (ADMM) is used for calculation. Extensive experiments demonstrated the proposed algorithm's effectiveness and compared it with state-of-the-art algorithms in subjective judgments and objective indicators. The experimental results fully demonstrate the proposed algorithm's superiority and efficacy.

Impact of energy saving on the financial performance of industrial enterprises in China: An empirical analysis based on propensity score matching.

Does energy-saving have a positive effect on the long-term development of enterprises? To answer this question, this study uses the propensity score matching (PSM) method to determine the impact of enterprises completing energy-saving objectives on their financial performance based on data from an industrial enterprise database in China. The results show that industrial enterprises that have completed the energy-saving target have advantages in profitability, operational and financial indicators but have deficiencies in debt indicators, and there is no significant difference in the ratio of profits to cost and expense. The research results of high energy-consuming industry are the same as the overall sample of industrial enterprises in terms of operational and financial indicators, and debt ratio indicators. Nevertheless, energy saving has no significant impact on profit and ratio of profits to cost of high energy-consuming industry.

The Bidirectional Association Between Physical and Cognitive Function Among Chinese Older Adults: A Mediation Analysis.

This study investigated the bidirectional association between physical and cognitive function in later life and examined the mechanisms underlying the interrelationship. We employed cross-lagged panel models to analyze a sample of 4232 unique participants aged 65 years and older from three waves of the Chinese Longitudinal Healthy Longevity Survey. Physical activity and social participation were tested as potential mediators between physical and cognitive function. Our findings revealed a reciprocal relationship between physical and cognitive function and a reciprocal relationship between physical and cognitive decline. Moreover, physical activity was confirmed to mediate the bidirectional association between physical and cognitive function, whereas social participation did not seem to be a mediator. A vicious cycle linking physical and cognitive decline may exist in Chinese older adults. However, leading a physically active lifestyle could be an effective intervention to slow physical and cognitive aging, thereby toning down the vicious cycle.

Multilevel regulation of RUVBL2 expression predicts poor prognosis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the second-most lethal cancer worldwide with a complex pathogenesis. RuvB-like 2 (RUVBL2) was previously found to contribute to hepatocarcinogenesis. However, its expression, regulation and clinical significance have not been systematically evaluated in a large number of clinical samples. METHODS: Here, we performed a comprehensive analysis of RUVBL2 based on multiple datasets from 371 liver cancer patients of The Cancer Genome Atlas (TCGA) and on immunohistochemical staining in 153 subjects. In addition, the aberrant signaling pathways caused by RUVBL2 overexpression were investigated. RESULTS: We demonstrated that promoter hypomethylation, copy number gain, MYC amplification and CTNNB1 mutation were all responsible for RUVBL2 overexpression in HCC. High levels of RUVBL2 mRNA were associated with shorter recurrence-free survival time (RFS) but not overall survival time (OS). Furthermore, RUVBL2 protein was overexpressed in the nucleus and cytoplasm of HCC samples. Univariate and multivariate survival analyses showed that strong nuclear and cytoplasmic staining of RUVBL2 independently predicted worse OS and RFS with a 2.03-fold and a 1.71-fold increase in the hazard ratio, respectively. High levels of RUVBL2 promoted carcinogenesis through the heat shock protein 90 (HSP90)-Cell Division Cycle 37 (CDC37), AKT serine/threonine kinase (AKT) and mitogen-activated protein kinase (ERK/MAPK) pathways. CONCLUSION: The deregulation of RUVBL2 in HCC is influenced at the genomic, epigenetic and transcriptional levels. Our findings highlight the potential roles of RUVBL2 as a promising prognostic marker as well as a therapeutic target for HCC.

Mutant p53 increases exosome-mediated transfer of miR-21-3p and miR-769-3p to promote pulmonary metastasis.

OBJECTIVE: Tumor metastasis is a complex, multistep process that depends on tumor cells and their communication with the tumor microenvironment. A p53 gain-of-function mutant has been shown to enhance the tumorigenesis, invasion, and metastasis abilities of tumor cells. This study aimed to investigate the roles of p53 R273H mutation in the tumor microenvironment. METHODS: The in vitro and in vivo effects of the p53 R273H mutant on the invasion and metastasis of HCT116 cells were investigated. Exosomes from wild-type and HCT116-TP53(R273H) cells were cocultured with mouse embryonic fibroblasts (MEFs). The roles of differentially expressed exosomal microRNAs identified by microarray analysis were investigated. The functions of the p53 R273H mutant in tumor cells were also investigated via gene expression microarray and quantitative polymerase chain reaction (qPCR) analyses. RESULTS: Introducing p53 R273H mutant into HCT116 cells significantly potentiated pulmonary metastasis in vivo. In the presence of exosomes derived from HCT116-TP53(R273H) cells, the exosomes were taken up by MEFs and became activated. Microarray analysis showed that the p53 R273H mutation increased the exosomal levels of miR-21-3p and miR-769-3p. Intriguingly, in clinical samples, miR-21-3p and miR-769-3p levels were significantly higher in patients with a p53 mutation than in those without this mutation. Furthermore, both miR-21-3p and miR-769-3p activated fibroblasts and exerted a synergistic effect via their target genes on the transforming growth factor-ß (TGF-ß)/Smad signaling pathway. The activated fibroblasts excreted cytokine TGF-ß and may have reciprocally induced cancer cells to undergo epithelial-mesenchymal transition (EMT). Indeed, HCT116-TP53(R273H) cells showed increased expression of ZEB1 and SNAI2 and decreased transcription of several cell adhesion molecules. CONCLUSIONS: The mutant p53-exosomal miR-21-3p/miR-769-3p-fibroblast-cytokine circuit appears to be responsible for communication between tumor and stromal cells, with exosomal miRNAs acting as a bridge. miR-21-3p and miR-769-3p are potential predictive markers of pulmonary metastasis and candidate targets for therapeutic interventions.

In-depth proteomic analysis of tissue interstitial fluid for hepatocellular carcinoma serum biomarker discovery.

BACKGROUND: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. New serum biomarkers for HCC screening are needed, especially for alpha-fetoprotein (AFP) negative patients. As a proximal fluid between body fluids and intracellular fluid, tissue interstitial fluid (TIF) is a suitable source for serum biomarker discovery. METHODS: Sixteen paired TIF samples from HCC tumour and adjacent non-tumour tissues were analysed by isobaric tags for relative and absolute quantitation (iTRAQ) method. Two proteins were selected for ELISA validation in serum samples. RESULTS: Totally, 3629 proteins were identified and 3357 proteins were quantified in TIF samples. Among them, 232 proteins were significantly upregulated in HCC-TIF and 257 proteins down-regulated. Two overexpressed extracellular matrix proteins, SPARC and thrombospondin-2 (THBS2) were selected for further validation. ELISA result showed that the serum levels of SPARC and THBS2 in HCC patients were both significantly higher than those in healthy controls. The combination of serum SPARC and THBS2 could distinguish HCC (AUC=0.97, sensitivity=86%, specificity=100%) or AFP-negative HCC (AUC=0.95, sensitivity=91%, specificity=93%) from healthy controls. And the combination of serum SPARC and THBS2 could also distinguish HCC patients from benign liver disease patients (AUC=0.93, sensitivity=80%, specificity=94%). In addition, serum THBS2 was found to be a novel independent indicator for poor prognosis of HCC. CONCLUSIONS: Novel HCC candidate serum markers were found through in-depth proteomic analysis of TIF, which demonstrated the successful utility of TIF in cancer serum biomarker discovery.

[Chinmedomics strategy to discover effective constituents and elucidate action mechanism of Nanshi capsule against kidney-yang deficiency syndrome].

The chinmedomics method was used to explore the effect of Nanshi capsule on endogenous metabolites of rats with kidney-yang deficiency syndrome, investigate the metabolites and metabolic pathways closely related to kidney-yang deficiency syndrome (KYDS)and identify the therapeutic basis of Nanshi capsule(NPC)as well as its action mechanism for KYDS. The routine biochemical indexes of serum were detected and histomorphology was observed. Based on the chinmedomics technology platform, discriminatory analysis in multivariate modes was conducted for rat blood and urine, thus to investigate the biomarkers of KYDS and the therapeutic effect of NPC against KYDS. Meanwhile, the main constituents of NPC in rat serum were also detected to analyze its correlation between the constituents in vivo and the biomarkers of KYDS, and determine the potential effective compounds for therapeutic effect. Eleven biomarkers of KYDS were identified in the rat models, involving steroid hormone biosynthesis, tryptophan metabolism and tyrosine metabolism. It was found that NPC could regulate steroid hormone biosynthesis, tryptophan metabolism and tyrosine metabolism; PCMS analysis showed that caffeic acid, 2-hydroxy-1-methoxy-anthraquinone, 1-hydroxy-2-methoxyanthraquinone, ferulic acid glucuronide conjugation, deacetylasperulosidic acid, cynaroside, betaine and umbelliferone were the main effective compounds of NPC for KYDS. In this study, cynaroside, betaine, umbelliferone and other compounds in NPC could integrally regulate the disturbance of metabolic profile in KYDS by improving the hormone synthesis, hormone synthesis pathway, hormone synthesis and release pathway in tyrosine metabolism and linoleic acid synthesis pathway in linoleic acid metabolism. These results indicated that the NPC had the characteristics of multi-pathway, multi-target and overall regulation in the treatment of KYDS. Chinmedomics approach can provide methodology support to discover innovative drug from traditional Chinese medicine.

Biomarker Discovery and Verification of Esophageal Squamous Cell Carcinoma Using Integration of SWATH/MRM.

We propose an efficient integration of SWATH with MRM for biomarker discovery and verification when the corresponding ion library is well established. We strictly controlled the false positive rate associated with SWATH MS signals and carefully selected the target peptides coupled with SWATH and MRM. We collected 10 samples of esophageal squamous cell carcinoma (ESCC) tissues paired with tumors and adjacent regions and quantified 1758 unique proteins with FDR 1% at protein level using SWATH, in which 467 proteins were abundance-dependent with ESCC. After carefully evaluating the SWATH MS signals of the up-regulated proteins, we selected 120 proteins for MRM verification. MRM analysis of the pooled and individual esophageal tissues resulted in 116 proteins that exhibited similar abundance response modes to ESCC that were acquired with SWATH. Because the ESCC-related proteins consisted of a high percentile of secreted proteins, we conducted the MRM assay on patient sera that were collected from pre- and postoperation. Of the 116 target proteins, 42 were identified in the ESCC sera, including 11 with lowered abundances postoperation. Coupling SWATH and MRM is thus feasible and efficient for the discovery and verification of cancer-related protein biomarkers.

ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the eighth most common cause of cancer-related death worldwide. However, previous genome-wide single nucleotide polymorphism association analyses have not explained the high heritability associated with ESCC. In this study, we performed genome-wide copy number variation (CNV) analysis on 128 discordant sibling pairs to identify novel genes that contribute to ESCC susceptibility. A total of 57 774 individual CNVs were identified, and an interactive network of common CNV-associated genes was constructed, which showed that several ABC transporter genes contain CNVs in ESCC patients. Independent validation of a CNV at 13q32.1 in 1048 northern Chinese Han subjects demonstrated that the amplification of ABCC4 significantly correlated with ESCC risk [odds ratio: 3.36 (1.65-7.93), P = 0.0013]. Immunohistochemistry staining suggested that high copy numbers correlated with increased protein levels. High expression of ABCC4 was an independent poor prognostic factor for ESCC [relative risk: 1.73 (1.10-2.73), P = 0.0181]. The CNV region showed strong enhancer activity. Furthermore, inhibition of ABCC4 protein in ESCC cells decreased cell proliferation and motility via the inhibition of COX-2, PGE2 receptors and c-Myc expression; AKT, extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation; and ß-catenin nuclear translocation in ESCC cells. In conclusion, the CNV at 13q32.1 is associated with ESCC susceptibility, and a gene within this locus, ABCC4, activates the oncogenic pathways in ESCC and thus facilitates cancer cell development and progression. A direct genetic contribution of ESCC risk through CNV common variants was determined in this study, and ABCC4 might therefore have predictive and therapeutic potential for ESCC.

[Detection of circulating tumor cells in patients with hepatocellular carcinoma].

OBJECTIVE: To explore the detection efficiency of circulating tumor cells (CTCs) in patients with hepatocellular carcinoma (HCC). METHODS: Immunomagnetic negative enrichment by nanometer magnetic beads and label-free capture with Captor(TM) system were used to isolate and enrich CTCs from peripheral blood of HCC patients, and epithelial and HCC markers were applied to identify CTCs by immunofluorescence staining. CTCs were detected in 50 HCC patients before and after hepatectomy to test the method for isolation, enrichment and identification. The dynamic changes of pre- and post-operative CTCs' numbers were compared. The clinical data were analyzed using SPSS 19.0 software. RESULTS: Negative enrichment methods by nanometer magnetic beads and label-free capture using Captor(TM) system were both suitable for CTCs isolation and enrichment in HCC patients. The positive detection rate of CTCs in HCC patients via negative enrichment was 96.0% (48/50), the preoperative median number of CTCs was 16 per 7.5 ml blood, and the postoperative median number was 17 per 7.5 ml blood. CONCLUSIONS: Both negative enrichment and Captor(TM) system are suitable for isolation and enrichment of CTCs in HCC patients. There is a significant difference in the numbers of CTCs before and after operation, and dynamic detection of CTCs will provide helpful prognostic information for HCC patients in clinics.

Efficacy of combining a medial superior malleolar perforator flap from the posterior tibial artery with a vacuum-assisted closure dressing for skin and soft tissue defects of the Achilles tendon area.

OBJECTIVE: This randomized clinical trial aimed to investigate the clinical efficacy of combining a medial superior malleolar perforator flap from the posterior tibial artery (PTAPF) with a vacuum-assisted closure (VAC) dressing for skin and soft tissue defects in the Achilles tendon area. METHODS: Twenty-eight patients were randomly divided into two equally sized groups: the control group received treatment with a medial superior malleolar perforator flap, while the experimental group was treated with a perforator flap from the posterior tibial artery in combination with a VAC dressing. Perioperative data, including average operative time, intraoperative blood loss, intraoperative complications, time to ambulation, and hospital stay after surgery, were recorded. Clinical outcomes were assessed based on the time to first weight-bearing walking, time to full weight-bearing activity, Visual Analog Scale (VAS) score, American Orthopaedic Foot and Ankle Society hindfoot and ankle score, and the range of motion for ankle plantar flexion. RESULTS: The patients were monitored for 3-12 months (average, 8.5), and it was observed that the flaps remained stable without enlargement, and their texture and color were similar to the surrounding tissue. Significantly enhanced postoperative indices were noted in the experimental group compared to the control group (P<0.05). CONCLUSION: The medial superior malleolar perforator flap from the posterior tibial artery, especially when combined with a VAC dressing, proves to be an effective method for repairing medium-sized skin defects in the Achilles tendon area. This approach offers several benefits, including a reliable blood supply, simplicity of the procedure, decreased damage to the donor site, improved aesthetic outcomes, and fewer postoperative complications.

Bias of AI-generated content: an examination of news produced by large language models.

Large language models (LLMs) have the potential to transform our lives and work through the content they generate, known as AI-Generated Content (AIGC). To harness this transformation, we need to understand the limitations of LLMs. Here, we investigate the bias of AIGC produced by seven representative LLMs, including ChatGPT and LLaMA. We collect news articles from The New York Times and Reuters, both known for their dedication to provide unbiased news. We then apply each examined LLM to generate news content with headlines of these news articles as prompts, and evaluate the gender and racial biases of the AIGC produced by the LLM by comparing the AIGC and the original news articles. We further analyze the gender bias of each LLM under biased prompts by adding gender-biased messages to prompts constructed from these news headlines. Our study reveals that the AIGC produced by each examined LLM demonstrates substantial gender and racial biases. Moreover, the AIGC generated by each LLM exhibits notable discrimination against females and individuals of the Black race. Among the LLMs, the AIGC generated by ChatGPT demonstrates the lowest level of bias, and ChatGPT is the sole model capable of declining content generation when provided with biased prompts.

Chlorine-induced Gas-Solid coupled corrosion behaviors of tube materials in high steam parameter MSW incinerator.

The fast development of the waste incineration industry requires deeper insights into heating surface corrosion behavior at higher operating parameters with complex corrosion sources. This research investigates the corrosion behaviors of three types of plates, namely SA210-C, TP310, and 12CrMoV, when subjected to simulated flue gas and fly ash deposition simultaneously at temperatures ranging from 500℃ to 620℃. The results indicate that the weight loss due to coupling corrosion was 2.5 to 84.5 times higher than that of gas-phase corrosion under the same operating conditions. Among the three stainless-steels, TP310 demonstrates superior corrosion resistance. It is worth noting that, under the gas-solid coupling corrosion conditions, we observed a distinct two-layer structure of corrosion products. Despite the fly ash simulants detaching over time, the two-layer structure remained unchanged. Based on the theory of eutectic molten salt formation, we propose that alkali metal chlorides only initiate the formation of the molten layer in the initial stage of corrosion. Furthermore, we offer additional suggestions for the mechanism of sustaining the molten layer in the absence of alkali metal chlorides.

Qualitative and quantitative expression status of the human chromosome 20 genes in cancer tissues and the representative cell lines.

Under the guidance of the Chromosome-centric Human Proteome Project (C-HPP), (1, 2) we conducted a systematic survey of the expression status of genes located at human chromosome 20 (Chr.20) in three cancer tissues, gastric, colon, and liver carcinoma, and their representative cell lines. We have globally profiled proteomes in these samples with combined technology of LC-MS/MS and acquired the corresponding mRNA information upon RNA-seq and RNAchip. In total, 323 unique proteins were identified, covering 60% of the coding genes (323/547) in Chr.20. With regards to qualitative information of proteomics, we overall evaluated the correlation of the identified Chr.20 proteins with target genes of transcription factors or of microRNA, conserved genes and cancer-related genes. As for quantitative information, the expression abundances of Chr.20 genes were found to be almost consistent in both tissues and cell lines of mRNA in all individual chromosome regions, whereas those of Chr.20 proteins in cells are different from tissues, especially in the region of 20q13.33. Furthermore, the abundances of Chr.20 proteins were hierarchically evaluated according to tissue- or cancer-related distribution. The analysis revealed several cancer-related proteins in Chr.20 are tissue- or cell-type dependent. With integration of all the acquired data, for the first time we established a solid database of the Chr.20 proteome.

Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma.

To date, the useful markers of hepatocellular carcinoma (HCC) remains incompletely developed. Here, we show that annexin A2 complement alpha-fetoprotein (AFP), a widely used liver cancer marker, in the serologically surveillance and early detection of HCC. First, differentially expressed proteins in HCC were identified using a subcellular proteomic approach. Annexin A2 was then selected for further verification. It was found to be overexpressed in HCC tissues (60.7%, 136/224). Using a self-established sandwich enzyme-linked immunosorbent assay, we found that annexin A2 significantly increased in the sera of HCC (n = 175, median, 24.75 ng/µl) compared with the healthy (n = 49, median, 16.69 ng/µl), benign tumors (n = 19, median, 19.92 ng/µl), hepatitis (n = 23, median, 6.48 ng/µl) and cirrhosis (n = 51, median, 7.39 ng/µl) controls and other malignant tumors (n = 87). Importantly, raised concentrations of annexin A2 were observed in 83.2% (79/95) of early stage (median, 24.32 ng/µl) and 78.4% (58/74) of AFP-negative (median, 24.09 ng/µl) patients. Annexin A2 alone had a better area under the receiver-operating characteristic curve (AUC = 0.79, 95% confidence interval: 0.73-0.85) in comparison with AFP (AUC = 0.73, 95% confidence interval: 0.66-0.80) in detecting of early stage HCC. Combining both markers notably improved the diagnostic efficiency of early HCC with an achieved sensitivity of 87.4%. Additionally, the expression characteristics of annexin A2 during hepatocarcinogenesis were detected in p21-HBx gene knockin transgenic mice model. The results showed that annexin A2 expression was substantially elevated in HCC-bearing mice, in accordance with the finding in human samples. In conclusion, annexin A2 may be an independent serological candidate for hepatitis B virus-related HCC, especially in the early stage cases with normal serum AFP.

Bidirectional Association Between Internet Use and Episodic Memory Among Older Adults: A Longitudinal Mediation Study.

Using nationally representative longitudinal data from three waves of the China Health and Retirement Longitudinal Study (CHARLS), we assessed whether social participation and mental health were channels through which internet use and episodic memory mutually influenced each other. Cross-lagged panel models with multiple mediators were employed for the mediation analysis. The results reveal that social participation and depressive symptoms were mechanisms underlying the internet-cognition interplay. Among men, an increased chance of contacting friends served as a pathway connecting internet use with better episodic memory. Conversely, men with better episodic memory were more likely to use the internet partially due to their higher chances of having contact with friends and engaging in group activities. Among women, engagement in group activities and depressive symptoms were two channels through which internet use and episodic memory positively influenced each other. Our findings provide practical implications for slowing cognitive aging and narrowing the digital divide.

MARCKSL1 interacted with F-actin to promote esophageal squamous cell carcinoma mobility by modulating the formation of invadopodia.

BACKGROUND: Emerging evidence indicates that myristoylated alanine-rich C kinase substrate like 1 (MARCKSL1) is involved in the progression of esophageal squamous cell carcinoma (ESCC). However, the underpinning mechanism is unclear. Here, we investigated the mechanisms involving MARCKSL1 in ESCC progression. METHODS: CCK8, Transwell and wound-healing assays were employed to test the effect of MARCKSL1 on proliferation, invasion and migration in vitro. Next, transcriptome profiling was conducted through RNA sequencing to reveal the underlying mechanism of MARCKSL1 in ESCC progression, which was subsequently verified by western blot and qPCR analysis. Moreover, immunofluorescence and gelatin degradation assays were performed to reveal the ability of MARCKSL1 to mediate invadopodia formation and extracellular matrix (ECM) degradation. Finally, the correlation between MARCKSL1 and the clinicopathological features of ESCC patients was assessed based on TCGA database analysis and immunohistochemistry staining of tissue microarrays. RESULTS: Knockdown of MARCKSL1 markedly attenuated the cell motility capacity of ESCC cells in vitro, while MARCKSL1 overexpression had the opposite effect. Transcriptomic analysis showed that MARCKSL1 mediated the mobility and migration of ESCC cells. In addition, overexpression of MARCKSL1 increased the colocalization of F-actin and cortactin at the frontier edge of migrating cells and ECM degradation. Furthermore, in ESCC patients, the mRNA level of MARCKSL1 in esophageal carcinomas (n = 182) was found to be notably higher than that in adjacent esophageal epithelia (n = 286) and the expression levels of MARCKSL1 in the tumor tissues (n = 811) were significantly increased compared to those in noncancerous esophageal tissues (n = 442) with a large sample size. Higher expression of MARCKSL1 was positively correlated with lymph node metastasis and associated with worse survival rates of patients with ESCC. CONCLUSION: MARCKSL1 promotes cell migration and invasion by interacting with F-actin and cortactin to regulate invadopodia formation and ECM degeneration. High MARCKSL1 expression is positively correlated with poor prognosis in ESCC patients with lymph node metastasis.

BACH1-induced ferroptosis drives lymphatic metastasis by repressing the biosynthesis of monounsaturated fatty acids.

Esophageal squamous cell carcinoma (ESCC) is one of the fatal malignancies worldwide. It has an increased propensity to metastasize via lymphogenous routes in an early stage. The prognosis of patients with lymph node metastases (LNM) is often worse than that of patients without metastases. Although several factors have been found to influence metastasis, the mechanisms of preference for specific metastatic routes remain poorly understood. Herein, we provide evidence that the intrinsic hypersensitivity of tumor cells to ferroptosis may proactively drive lymphatic metastasis. Serum autoantibodies associated with LNM of early ESCC were screened using a whole-proteome protein array containing 19 394 human recombinant proteins, and an anti-BACH1 autoantibody was first identified. Pan-cancer analysis of ferroptosis-related genes with preferential lymphatic metastasis and preferential hematogenous metastasis based on The Cancer Genome Atlas data was performed. Only BACH1 showed significant overexpression in tumors with preferential lymphatic metastasis, whereas it was downregulated in most tumors with preferential nonlymphatic metastasis. In addition, it was found that the serum levels of autoantibodies against BACH1 were elevated in early-stage patients with LNM. Interestingly, BACH1 overexpression and ferroptosis induction promoted LNM but inhibited hematogenous metastasis in mouse models. Transcriptomic and lipidomic analyses found that BACH1 repressed SCD1-mediated biosynthesis of monounsaturated fatty acids, especially oleic acid (OA). OA significantly attenuated the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. OA addition significantly rescued the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. Importantly, the concentration gradient of OA between primary lesions and the lymph resulted in the chemoattraction of tumor cells to promote invasion, thus facilitating lymphatic metastasis. BACH1-induced ferroptosis drives lymphatic metastasis via the BACH1-SCD1-OA axis. More importantly, this study confirms that ferroptosis is a double-edged sword in tumorigenesis and tumor progression. The clinical application of ferroptosis-associated agents requires a great caution.

Tumor-derived proliferative CTCs and CTC clusters predict aggressiveness and early recurrence in hepatocellular carcinoma patients.

BACKGROUND: Circulating tumor cells (CTCs), an indispensable liquid biopsy classifier, can provide extra information for the diagnosis and prognosis of hepatocellular carcinoma (HCC). METHODS: We systematically analyzed the peripheral blood of preoperative HCC patients (n = 270) for CTC number, Ki67 index reflecting the proliferative CTC percentage (PCP), and CTC clusters correlated with the characteristics of malignant HCC tumors. RESULTS: Driver gene mutations were found with high levels of consistency between CTCs and primary tumors (n = 73). CTC number and PCP were associated with tumor size, microvascular invasion (MVI), presence or absence of multiple tumors, and thrombosis significantly. CTC number and PCP robustly separated patients with and without relapse, with a sensitivity of 88.89%/81.48% and a specificity of 72.73%/94.81% in the training set (n = 104) and corresponding values of 80.00%/86.67% and 78.38%/89.19% in the validation set (n = 52), showing a better performance than that associated with the alpha-fetoprotein (AFP) level. CTC number, PCP, CTC clusters, and MVI were independent significant risk factors for HCC recurrence (P = 0.0375, P < 0.0001, P = 0.0017, and P = 0.0157). A nomogram model based on these risk factors showed a considerable prediction ability for HCC recurrence (area under the curve = 0.947). PCP (training: log-rank P < 0.0001; hazard ratio [HR] 30.13, 95% confidence interval [CI] = 11.12-81.62; validation: log-rank P < 0.0001; HR 25.73, 95% CI = 5.28-106.60) and CTC clusters (training: log-rank P < 0.0001; HR 17.34, 95% CI = 7.46-40.30; validation: log-rank P < 0.0001; HR 9.92, 95% CI = 2.55-38.58) were more significantly correlated with worse recurrence-free survival than CTC number (training: log-rank P < 0.0001; HR 14.93, 95% CI = 4.48-49.78; validation: log-rank P = 0.0007; HR 9.03, 95% CI = 2.53-32.24). CONCLUSION: PCP and CTC clusters may predict HCC recurrence and improve the performance of the serum biomarker AFP.