Molecular characteristics of early-onset compared with late-onset colorectal cancer: A case controlled study.

BACKGROUND: Early-Onset Colorectal Cancer (EOCRC) is associated with a poorer prognosis relative to Late-Onset Colorectal Cancer (LOCRC), and its incidence has witnessed a gradual escalation in recent years. This necessitates a comprehensive examination of the underlying pathogenesis and the identification of therapeutic targets specific to EOCRC patients. The present study aimed to delineate the distinct molecular landscape of EOCRC by juxtaposing it with that of LOCRC. METHODS: A total of 11,344 colorectal cancer patients, diagnosed between 2003 and 2022, were enrolled in this study, comprising 578 EOCRC cases and 10,766 LOCRC cases. Next-generation sequencing technology was employed to assess the tumor-related mutation and tumor mutation burden (TMB) in these patients. PD-L1 expression was quantified using immunohistochemistry. Microsatellite instability (MSI) was determined via capillary electrophoresis (2B3D NCI Panel). RESULTS: Upon comparing LOCRC with EOCRC patients, the latter group demonstrated a tendency towards advanced TNM stage, lower tumor differentiation, and less favorable histological types. Among LOCRC patients, those with MSI-H status were found to have an earlier TNM stage compared to those with MSI-L/MSS status. Significantly, the incidence of MSI-H was notably higher in EOCRC (10.2%) compared to LOCRC (2.2%). Mutations in the 7-gene panel (ARID1A, FANCI, CASP8, DGFRA, DPYD, TSHR, and PRKCI) were more prevalent in LOCRC. Within the EOCRC cohort, patients with the MSI-H subtype displayed an earlier TNM stage but concurrently exhibited poorer tissue differentiation and a higher frequency of mucinous adenocarcinoma. Among EOCRC patients, FBXW7, FAT1, ATM, ARID1A, and KMT2B mutations were significantly enriched in the MSI-H subgroup. A comparative analysis of MSI-H patients revealed heightened mutation frequencies of FGFBR2, PBRM1, RNF43, LRP1B, FBXW7, ATM, and ARID1A in the EOCRC group. Furthermore, EOCRC patients demonstrated a higher overall TMB, particularly in the MSI-H subtype. PD-L1 expression was elevated in EOCRC and positively associated with MSI status. CONCLUSIONS: This study revealed a significantly higher MSI-H distribution rate in early-onset colorectal cancer, and EOCRC exhibits a distinct mutational signature coupled with higher PD-L1 expression. These findings hold promise in guiding personalized therapeutic strategies for improved disease management in EOCRC patients.

Evaluating AI in medicine: a comparative analysis of expert and ChatGPT responses to colorectal cancer questions.

Colorectal cancer (CRC) is a global health challenge, and patient education plays a crucial role in its early detection and treatment. Despite progress in AI technology, as exemplified by transformer-like models such as ChatGPT, there remains a lack of in-depth understanding of their efficacy for medical purposes. We aimed to assess the proficiency of ChatGPT in the field of popular science, specifically in answering questions related to CRC diagnosis and treatment, using the book "Colorectal Cancer: Your Questions Answered" as a reference. In general, 131 valid questions from the book were manually input into ChatGPT. Responses were evaluated by clinical physicians in the relevant fields based on comprehensiveness and accuracy of information, and scores were standardized for comparison. Not surprisingly, ChatGPT showed high reproducibility in its responses, with high uniformity in comprehensiveness, accuracy, and final scores. However, the mean scores of ChatGPT's responses were significantly lower than the benchmarks, indicating it has not reached an expert level of competence in CRC. While it could provide accurate information, it lacked in comprehensiveness. Notably, ChatGPT performed well in domains of radiation therapy, interventional therapy, stoma care, venous care, and pain control, almost rivaling the benchmarks, but fell short in basic information, surgery, and internal medicine domains. While ChatGPT demonstrated promise in specific domains, its general efficiency in providing CRC information falls short of expert standards, indicating the need for further advancements and improvements in AI technology for patient education in healthcare.

Uncovering the complex regulatory network of spring bud sprouting in tea plants: insights from metabolic, hormonal, and oxidative stress pathways.

The sprouting process of tea buds is an essential determinant of tea quality and taste, thus profoundly impacting the tea industry. Buds spring sprouting is also a crucial biological process adapting to external environment for tea plants and regulated by complex transcriptional and metabolic networks. This study aimed to investigate the molecular basis of bud sprouting in tea plants firstly based on the comparisons of metabolic and transcriptional profiles of buds at different developmental stages. Results notably highlighted several essential processes involved in bud sprouting regulation, including the interaction of plant hormones, glucose metabolism, and reactive oxygen species scavenging. Particularly prior to bud sprouting, the accumulation of soluble sugar reserves and moderate oxidative stress may have served as crucial components facilitating the transition from dormancy to active growth in buds. Following the onset of sprouting, zeatin served as the central component in a multifaceted regulatory mechanism of plant hormones that activates a range of growth-related factors, ultimately leading to the promotion of bud growth. This process was accompanied by significant carbohydrate consumption. Moreover, related key genes and metabolites were further verified during the entire overwintering bud development or sprouting processes. A schematic diagram involving the regulatory mechanism of bud sprouting was ultimately proposed, which provides fundamental insights into the complex interactions involved in tea buds.

Detection of infrared small target based on background subtraction local contrast measure and Gaussian structural similarity.

Infrared (IR) small target detection, especially in a complex background, continues to present challenges in the low false alarm rate and high robustness. In this paper, a background subtraction local contrast measure (BSLCM) and Gaussian structural similarity (GSS) integrated structural model is proposed to detect IR small target. In the proposed model, BSLCM is used to suppress the complex background and enhance the target. GSS calculation is conducted to eliminate the high-brightened background residual and noise further. To evaluate the performance of the proposed method, real IR sequences and seven state-of-the-art (SOTA) methods were adopted. The results demonstrated that the BSLCM can suppress all types of strong background clutter and enhance the true target effectively.

Polysaccharides from Fu brick tea ameliorate obesity by modulating gut microbiota and gut microbiota-related short chain fatty acid and amino acid metabolism.

Fu brick tea (FBT) is a traditional tea manufactured by solid-state fermentation of tea leaves (Camellia sinensis). Although anti-obesity effects have been reported for FBT, the associated role of FBT polysaccharides (PSs) and the underlying mechanisms remain unknown. In this study, we found that FBTPSs inhibited obesity, hyperlipidemia, and inflammation; improved intestinal barrier function; and alleviated gut microbiota dysbiosis in high-fat diet-fed rats. Akkermansia muciniphila, Bacteroides, Parasutterella, Desulfovibrio, and Blautia were the core microbes regulated by FBTPSs. FBTPSs regulated the production of gut microbiota-related metabolites, including short-chain fatty acids (SCFAs), branched-chain amino acids, and aromatic amino acids throughout the development of obesity, and regulated the SCFA-GPR signaling pathway. FBTPS-treated fecal microbiota transplant ameliorated obesity, alleviated gut microbiota dysbiosis, and improved gut microbiota-associated metabolites, suggesting that the anti-obesity effect of FBTPSs was gut microbiota-dependent. FBTPSs may serve as novel prebiotic agents for the treatment of obesity and dysbiosis of gut microbiota.

GPR176 Promotes Cancer Progression by Interacting with G Protein GNAS to Restrain Cell Mitophagy in Colorectal Cancer.

GPR176 belongs to the G protein-coupled receptor superfamily, which responds to external stimuli and regulates cancer progression, but its role in colorectal cancer (CRC) remains unclear. In the present study, expression analyses of GPR176 are performed in patients with colorectal cancer. Genetic mouse models of CRC coupled with Gpr176-deficiency are investigated, and in vivo and in vitro treatments are conducted. A positive correlation between GPR176 upregulation and the proliferation and poor overall survival of CRC is demonstrated. GPR176 is confirmed to activate the cAMP/PKA signaling pathway and modulate mitophagy, promoting CRC oncogenesis and development. Mechanistically, the G protein GNAS is recruited intracellularly to transduce and amplify extracellular signals from GPR176. A homolog model tool confirmed that GPR176 recruits GNAS intracellularly via its transmembrane helix 3-intracellular loop 2 domain. The GPR176/GNAS complex inhibits mitophagy via the cAMP/PKA/BNIP3L axis, thereby promoting the tumorigenesis and progression of CRC.

METTL3-mediated Hsa_circ_0000390 downregulation enhances the proliferation, migration, and invasion of colorectal cancer cells by increasing Notch1 expression.

Circular RNAs (circRNAs), as noncoding RNAs, have gained widespread attention in cancers. Circ_0000390 has been verified to be downregulated in gastric cancer, while its function and regulatory mechanism in cancer is largely unknown. The purpose of this study is to investigate the expression, functions, and potential mechanism of circ_0000390 in colorectal cancer (CRC). Circ_0000390 expression in CRC tissues was first identified with RT-qPCR. Besides, the function of circ_0000390 was assessed through gain-of-function and rescued experiments in CRC cells and mouse xenograft models. Our results showed that circ_0000390 was lowly expressed in CRC tissues, and circ_0000390 could downregulate Notch1 and be downregulated by METTL3. Functionally, results showed circ_0000390 overexpression suppressed the proliferation, cell migration, and invasion of CRC cells, which also could be reversed by Notch1 overexpression. Additionally, METTL3 overexpression could accelerate the proliferation, cell migration, and invasion of CRC cells, which also was weakened by circ_0000390 overexpression in CRC cells in vitro and in vivo. This study suggested that circ_0000390 might be anti-tumor factor in CRC and METTL3/Notch1 might be a therapeutic targets for CRC.

RP11-40C6.2 Inactivates Hippo Signaling by Attenuating YAP1 Ubiquitylation in Hepatitis B Virus-associated Hepatocellular Carcinoma.

Background and Aims: Chronic hepatitis caused by hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). We investigated the roles of oncogenic HBV infection-associated long noncoding RNAs in HCC. Methods: Bioinformatics analysis of data from the Cancer Genome Atlas (TCGA) was performed to screen potential oncogenic HBV-related lncRNAs. Next, we assessed their expression in clinical samples and investigated their correlation with clinical characteristics. The detailed oncogenic effects were analyzed by performing in vitro and in vivo studies. Results: RP11-40C6.2, an HBV infection-related lncRNA, was identified by analysis of the TCGA-Liver Hepatocellular Carcinoma database. Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of differentially expressed genes revealed a strong association of RP11-40C6.2 with the Hippo signaling pathway. RP11-40C6.2 was overexpressed in HCC patients with HBV infection compared to those without HBV infection. RP11-40C6.2 transcription showed a positive association with HBV-X protein (HBx), but not HBV core protein (HBc) expression, both of which are carcinogenic proteins. Luciferase gene reporter and ChIP assays revealed that YAP1/TAZ/TEADs complex enhanced RP11-40C6.2 transcription by binding to its promoter area. RP11-40C6.2 showed oncogenic characteristics in HCC cell lines and in animal models that were mediated via activation of YAP1. In vitro ubiquitylation assay revealed that RP11-40C6.2 can promote the stabilization of YAP1 by stopping phosphorylation at its s127 residue and further stopping its degradation through binding to 14-3-3. Conclusions: RP11-40C6.2 is an HBV infection-related lncRNA that exerts its oncogenic effects by targeting the Hippo signaling pathway.

UBE2J1 inhibits colorectal cancer progression by promoting ubiquitination and degradation of RPS3.

Ubiquitin-conjugating enzyme E2 J1 (UBE2J1) has been proven to participate in the ubiquitination of multiple substrate proteins. However, the underlying mechanisms of UBE2J1 as a ubiquitin-conjugating enzyme participating in cancer development and progression remain largely unknown. Here, we identified that UBE2J1 is downregulated in colorectal cancer (CRC) tissues and cell lines which are mediated by DNA hypermethylation of its promoter, and decreased UBE2J1 is associated with poor prognosis. Functionally, UBE2J1 serving as a suppressor gene inhibits the proliferation and metastasis of CRC cells. Mechanistically, UBE2J1-TRIM25, forming an E2-E3 complex, physically interacts with and targets RPS3 for ubiquitination and degradation at the K214 residue. The downregulated RPS3 caused by UBE2J1 overexpression restrains NF-κB translocation into the nucleus and therefore inactivates the NF-κB signaling pathway. Our study revealed a novel role of UBE2J1-mediated RPS3 poly-ubiquitination and degradation in disrupting the NF-κB signaling pathway, which may serve as a novel and promising biomarker and therapeutic target for CRC.

The landscape of micron-scale particles including microplastics in human enclosed body fluids.

Exogenous microparticles including microplastics are novel pollutants that could persist in the environment with potential health effects, while crucial data on their exposure in humans are still lacking. To understand the panorama of microparticles including microplastics exposure and distribution characteristics in different kinds of body fluids. A non-targeted microparticle internal exposure landscape analysis was done in thirteen kinds of human enclosed body fluids covering eight body systems. Totally 104 patients aged 24-96 years with an average age of 56 years were included in this study. After sample digestion, non-soluble microparticles were detected and identified with one Raman Microspectroscope under a strict quality control-particle detection system. Totally 702 microparticles with size ranging from 2.15 to 103.27 µm were detected in samples. Microparticles were identified into 84 substances or 66 molecules, most of which were firstly reported inside human body. Nine kinds of microplastics were originally reported in human body fluids with their size ranging from 19.66 to 103.27 µm. Microparticles exposure was unexpectedly high inside the human body despite the protection of biological barriers and membranes, raising awareness of the impact of particle pollution on sustainable development.

Acetyltransferase NAT10 regulates the Wnt/ß-catenin signaling pathway to promote colorectal cancer progression via ac4C acetylation of KIF23 mRNA.

BACKGROUND: N4-acetylcytidine (ac4C) as a significant RNA modification has been reported to maintain the stability of mRNA and to regulate the translation process. However, the roles of both ac4C and its 'writer' protein N-acetyltransferase 10 (NAT10) played in the disease especially colorectal cancer (CRC) are unclear. At this point, we discover the underlying mechanism of NAT10 modulating the progression of CRC via mRNA ac4C modification. METHODS: The clinical significance of NAT10 was explored based on the TCGA and GEO data sets and the 80 CRC patients cohort of our hospital. qRT-PCR, dot blot, WB, and IHC were performed to detect the level of NAT10 and ac4C modification in CRC tissues and matched adjacent tissues. CCK-8, colony formation, transwell assay, mouse xenograft, and other in vivo and in vitro experiments were conducted to probe the biological functions of NAT10. The potential mechanisms of NAT10 in CRC were clarified by RNA-seq, RIP-seq, acRIP-seq, luciferase reporter assays, etc. RESULTS: The levels of NAT10 and ac4C modification were significantly upregulated. Also, the high expression of NAT10 had important clinical values like poor prognosis, lymph node metastasis, distant metastasis, etc. Furthermore, the in vitro experiments showed that NAT10 could inhibit apoptosis and enhance the proliferation, migration, and invasion of CRC cells and also arrest them in the G2/M phase. The in vivo experiments discovered that NAT10 could promote tumor growth and liver/lung metastasis. In terms of mechanism, NAT10 could mediate the stability of KIF23 mRNA by binding to its mRNA 3'UTR region and up-regulating its mRNA ac4c modification. And then the protein level of KIF23 was elevated to activate the Wnt/ß-catenin pathway and more ß-catenin was transported into the nucleus which led to the CRC progression. Besides, the inhibitor of NAT10, remodelin, was applied in vitro and vivo which showed an inhibitory effect on the CRC cells. CONCLUSIONS: NAT10 promotes the CRC progression through the NAT10/KIF23/GSK-3ß/ß-catenin axis and its expression is mediated by GSK-3ß which forms a feedback loop. Our findings provide a potential prognosis or therapeutic target for CRC and remodelin deserves more attention.

CircMYH9 increases KPNA2 mRNA stability to promote hepatocellular carcinoma progression in an EIF4A3-dependent manner.

Hepatocellular carcinoma (HCC) is the most commonly diagnosed cancer worldwide with a high incidence of recurrence and metastasis; however, the molecular mechanisms underlying HCC development remain to be fully understood. In this study, we identified circMYH9 as an important regulator of HCC. Overexpression of circMYH9 induced, while knockdown of circMYH9 inhibited, the proliferation, migration, and invasion of HCC cells. Mechanistically, circMYH9 bound to eukaryotic translation initiation factor 4A3 (EIF4A3) and increased karyopherin subunit alpha 2 (KPNA2) mRNA stability. circMYH9 knockdown in HCC cells reduced the stability of KPNA2 mRNA. Importantly, circMYH9 regulation of HCC required the activity of KPNA2. In support with this, circMYH9 level was positively correlated with the expression of KPNA2 in HCC patient samples. Taken together, our study was the first to uncover the oncogenic role of circMYH9 in HCC and further elucidated the functional mechanism of circMYH9 by interacting with EIF4A3 to increase KPNA2 mRNA stability. Our findings might provide a novel potential target for the diagnose and treatment of HCC.

CircASPH Promotes Hepatocellular Carcinoma Progression Through Methylation and Expression of HAO2.

CircRNAs have been reported to be related to hepatocellular carcinoma (HCC) development. Limited studies have revealed the expression profile of circRNAs in tumor and para-tumor normal samples in HCC patients. We found that circASPH was significantly increased in HCC tumor samples and that the level of circASPH was closely related to the overall survival of HCC patients. Mechanistically, circASPH could regulate the methylation of the promoter and expression of hydrocyanic oxidase 2 (HAO2) to promote HCC progression by acting as a sponge for miR-370-3p, and miR-370-3p could target DNMT3b and increase the 5mC level. In summary, our study determined that circASPH could regulate the methylation and expression of HAO2 and it could be considered an important epigenetic regulator in HCC progression.

Upregulated circTMEM59 Inhibits Cell Growth and Metastasis by miR-668-3p/ID4 Axis in Colorectal Cancer.

The incidence and mortality of colorectal cancer (CRC) are ranked in the top three worldwide in 2020. Abundant studies have reported that circular RNAs (circRNAs) act critical roles in the genesis and development of tumors, including CRC. Nevertheless, the roles and detailed regulation mechanisms of circRNAs that are related to the initiation and development of CRC have not been fully found and clarified. This research primarily revealed that circTMEM59 was greatly downregulated in CRC tissues and cell lines via qRT-PCR. In addition, the decreased expression of circTMEM59 was closely related to adverse clinicopathological characteristics and the shorter survival time of CRC patients. Then, a further study found that the overexpression of circTMEM59 suppressed cell growth and accelerated the cell death of CRC via a series of experiments in vitro and in vivo. Furthermore, circTMEM59 also repressed the metastatic behaviors of CRC cells. Further study revealed that circTMEM59 played the role of competing endogenous RNAs (ceRNAs) by binding to miR-668-3p to increase the expression of inhibitor of DNA binding 4 (ID4) in CRC. In summary, the results of this study clarified the antitumor effects of circTMEM59/miR-668-3p/ID4 axis in CRC progression and provided potential therapeutic targets and clinical prognostic markers for CRC.

Total Mesorectal Excision vs. Transanal Endoscopic Microsurgery Followed by Radiotherapy for T2N0M0 Distal Rectal Cancer: A Multicenter Randomized Trial.

INTRODUCTION: Transanal endoscopic microsurgery (TEM) is an organ-preserving treatment alternative for patients with early rectal cancer. However, TEM alone is associated with greater risk of local recurrence and inferior survival in comparison with total meso-rectal excision (TME). As an important adjuvant therapy, radiotherapy can effectively reduce the local recurrence rate of rectal cancer. This study aimed to investigate whether TEM followed by radiotherapy can be a valid alternative to TME in T2N0M0 distal rectal cancer treatment. METHODS: We plan to recruit 168 participants meeting established inclusion criteria. Following informed consent, participants will randomly receive treatment protocols of TEM followed by radiotherapy (a total dose of 45-50.4 Gy given in 25-28 factions) or TME. Depending on post-operative pathology, the participants will receive either long-term follow-up or further treatment. The primary endpoint of this trial is 3-year local recurrence rate. The secondary end points include 3-year disease-free survival rate, 3-year overall survival rate, 3-year mortality rate, post-operative quality of life, post-operative safety index, intraoperative evaluation index and post-operative short-term evaluation index. DISCUSSION: This trial is the first prospective randomized trial to investigate the rectum preserving treatment by using transanal local excision followed by radiotherapy. CLINICAL TRIAL REGISTRATION: The trial was prospectively registered at ClinicalTrials.gov NCT04098471 on September 20, 2019.

Correction: The attenuated hepatocellular carcinoma-specific Listeria vaccine Lmdd-MPFG prevents tumor occurrence through immune regulation of dendritic cells.

[This corrects the article DOI: 10.18632/oncotarget.3558.].

Long non-coding RNA CCDC144NL-AS1 promotes cell proliferation by regulating the miR-363-3p/GALNT7 axis in colorectal cancer.

Colorectal cancer (CRC) is a burdensome health concern worldwide. Long non-coding RNA (lncRNA) have emerged as vital roles in multiple cancers, including CRC. Increasing evidence has demonstrated that lncRNA CCDC144NL-AS1 acts crucial roles in tumor developments. Nevertheless, its role in CRC remains largely unknown. The level of CCDC144NL-AS1 expression was detected in 100 CRC tissues and paired adjacent tissues. The gain- and loss-of-function experiments were conducted to investigate the biological functions of CCDC144NL-AS1 in vitro and in vivo. The potential mechanism of CCDC144NL-AS1 exerting as competing endogenous RNAs (ceRNAs) was demonstrated by bioinformatics, luciferase reporter assay and in vitro experiments. CCDC144NL-AS1 was up-regulated in CRC tissues and cells. High CCDC144NL-AS1 was connected with the adverse clinicopathological features and worse prognosis of CRC. Furthermore, knockdown of CCDC144NL-AS inhibited the cell proliferation and led to the cell cycle G0-1/S arrest, whereas upregulated CCDC144NL-AS1 obtained the inverse results. Further study found that CCDC144NL-AS1 functioned as ceRNAs in regulating CRC proliferation. MiR-363-3p was the target of CCDC144NL-AS1, which sponges GALNT7 in regulating cell growth of CRC. The study demonstrated that the CCDC144NL-AS1/miR-363-3p/GALNT7 axis exerts on key roles in cell proliferation and presents an emerging target for CRC therapy and prognostic biomarker.

Mid-wave infrared polarization detection of ship targets for small temperature difference conditions.

Ship detection under small temperature difference conditions is an important research direction for infrared (IR) detection of typical targets at present. To solve the problems of low contrast and difficult recognition of ship IR imaging due to small temperature differences, the degree of polarization (DOP) images is applied to the field of low-temperature aberration imaging based on the polarization principle. Meanwhile, the misalignment problem caused by the lens jitter in the polarization calculation is solved by the proposed mutual information iterative algorithm. We demonstrate improvement in the target/background local contrast of low-temperature aberration imaging by using the difference in polarization characteristics between the target and the background. The effectiveness of the method was verified by experiments. The results show that the contrast of DOP images combined with multi-angle polarization information is about 30 times higher indoors and three times higher outdoors than IR intensity images. Therefore, the IR polarization detection technique based on DOP images can effectively deal with the problem of low imaging contrast caused by small temperature differences.