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BACKGROUND: Owing to the lack of evidence-based medical studies with large sample sizes, the surgical approach for the radical resection of rectal neuroendocrine tumors remains controversial. METHODS: We retrospectively collected the medical records of patients with rectal neuroendocrine tumors who underwent radical resection at 17 large tertiary care hospitals in China between January 1, 2010, and April 30, 2022. All patients were divided into laparoscopic and open surgery groups. After propensity score matching to reduce confounders, the postoperative and oncologic outcomes were compared between the groups. RESULTS: We enrolled 174 patients with rectal neuroendocrine tumors who underwent radical surgery. After random matching, 124 patients were included in the comparison (62, laparoscopic surgery group; 62, open surgery group). The laparoscopic surgery group had fewer complications (14.5% vs. 35.5%, P = 0.007) and superior relapse-free survival (P = 0.048). Subgroup analysis revealed that the laparoscopic surgery group had fewer complications (10.9% vs. 34.7%, P = 0.004), shorter postoperative hospital stays (9.56 ± 5.21 days vs. 12.31 ± 8.61 days, P = 0.049) and superior relapse-free survival (P = 0.025) in the rectal neuroendocrine tumors ≤ 4 cm subgroup. CONCLUSIONS: Laparoscopic surgery was associated with improved postoperative outcomes and oncologic prognosis for patients with rectal neuroendocrine tumors ≤ 4 cm; it can serve as a safe and feasible option for radical surgery of rectal neuroendocrine tumors.
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Laparoscopía , Tumores Neuroendocrinos , Neoplasias del Recto , Humanos , Neoplasias del Recto/cirugía , Neoplasias del Recto/patología , Neoplasias del Recto/mortalidad , Laparoscopía/métodos , Laparoscopía/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Anciano , Resultado del Tratamiento , Adulto , China/epidemiología , Puntaje de Propensión , Tiempo de Internación/estadística & datos numéricosRESUMEN
The RNA modification, 5-methylcytosine (m5C), has recently gained prominence as a pivotal post-transcriptional regulator of gene expression, intricately intertwined with various tumorigenic processes. However, the exact mechanisms governing m5C modifications during the onset and progression of colorectal cancer (CRC) remain unclear. Here, it is determined that the m5C methyltransferase NSUN2 exhibits significantly elevated expression and exerts an oncogenic function in CRC. Mechanistically, NSUN2 and YBX1 are identified as the "writer" and "reader" of ENO1, culminating in the reprogramming of the glucose metabolism and increased production of lactic acid in an m5C-dependent manner. The accumulation of lactic acid derived from CRC cells, in turn, activates the transcription of NSUN2 through histone H3K18 lactylation (H3K18la), and induces the lactylation of NSUN2 at the Lys356 residue (K356), which is crucial for capturing target RNAs. Together, these findings reveal an intriguing positive feedback loop involving the NSUN2/YBX1/m5C-ENO1 signaling axis, thereby bridging the connection between metabolic reprogramming and epigenetic remodeling, which may shed light on the therapeutic potential of combining an NSUN2 inhibitor with immunotherapy for CRC.
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Neoplasias Colorrectales , Proteínas de Unión al ADN , Progresión de la Enfermedad , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Humanos , Ratones , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Animales , Retroalimentación Fisiológica , Metiltransferasas/metabolismo , Metiltransferasas/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Modelos Animales de Enfermedad , Fosfopiruvato Hidratasa , Biomarcadores de TumorRESUMEN
Clustered regularly interspaced palindromic repeats (CRISPR)-based technology, a powerful toolset for the unbiased functional genomic screening of biological processes, has facilitated several scientific breakthroughs in the biomedical field. Cancer immunotherapy has advanced the treatment of numerous malignancies that previously had restricted treatment options or unfavorable outcomes. In the realm of cancer immunotherapy, the application of CRISPR/CRISPR-associated protein 9 (Cas9)-based genetic perturbation screening has enabled the identification of genes, biomarkers, and signaling pathways that govern various cancer immunoreactivities, as well as the development of effective immunotherapeutic targets. In this review, we summarize the advances in CRISPR/Cas9-based screening for cancer immunotherapy and outline the immunotherapeutic targets identified via CRISPR screening based on cancer-type classification.
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Sistemas CRISPR-Cas , Inmunoterapia , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/diagnóstico , Inmunoterapia/métodos , Animales , Edición Génica/métodos , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: Tumors that resist anoikis, a programmed cell death triggered by detachment from the extracellular matrix, promote metastasis; however, the role of anoikis-related genes (ARGs) in colorectal cancer (CRC) stratification, prognosis, and biological functions remains unclear. METHODS: We obtained transcriptomic profiles of CRC and 27 ARGs from The Cancer Genome Atlas, the Gene Expression Omnibus, and MSigDB databases, respectively. CRC tissue samples were classified into two clusters based on the expression pattern of ARGs, and their functional differences were explored. Hub genes were screened using weighted gene co-expression network analysis, univariate analysis, and least absolute selection and shrinkage operator analysis, and validated in cell lines, tissues, or the Human Protein Atlas database. We constructed an ARG-risk model and nomogram to predict prognosis in patients with CRC, which was validated using an external cohort. Multifaceted landscapes, including stemness, tumor microenvironment (TME), immune landscape, and drug sensitivity, between high- and low-risk groups were examined. RESULTS: Patients with CRC were divided into C1 and C2 clusters. Cluster C1 exhibited higher TME scores, whereas cluster C2 had favorable outcomes and a higher stemness index. Eight upregulated hub ARGs (TIMP1, P3H1, SPP1, HAMP, IFI30, ADAM8, ITGAX, and APOC1) were utilized to construct the risk model. The qRT-PCR, Western blotting, and immunohistochemistry results were consistent with those of the bioinformatics analysis. Patients with high risk exhibited worse overall survival (p < 0.01), increased stemness, TME, immune checkpoint expression, immune infiltration, tumor mutation burden, and drug susceptibility compared with the patients with low risk. CONCLUSION: Our results offer a novel CRC stratification based on ARGs and a risk-scoring system that could predict the prognosis, stemness, TME, immunophenotypes, and drug susceptibility of patients with CRC, thereby improving their prognosis. This stratification may facilitate personalized therapies.
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Anoicis , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Anoicis/genética , Pronóstico , Microambiente Tumoral/genética , Masculino , Biomarcadores de Tumor/genética , Nomogramas , Femenino , Transcriptoma , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Studies on grade 2 rectal neuroendocrine tumors are limited, and the optimal treatment for these tumors is not well established. OBJECTIVE: We aimed to compare the oncologic results of local excision versus radical resection for the treatment of grade 2 rectal neuroendocrine tumors. DESIGN: Retrospective multicenter propensity score-matched study to minimize heterogeneity between groups and focus on the differences between surgery strategies. SETTINGS: Seventeen large-scale Chinese medical centers participated in this study. PATIENTS: A total of 144 patients with pathologically confirmed grade 2 rectal neuroendocrine tumors were retrospectively analyzed. MAIN OUTCOME MEASURES: Cancer-specific survival and relapse-free survival were assessed to compare surgery strategies. RESULTS: A total of 144 patients with grade 2 rectal neuroendocrine tumors were enrolled in this study. Twenty-seven patients underwent endoscopic resection, 55 underwent transanal excision, 50 underwent radical resection, and 12 underwent palliative surgery or biopsy for distant metastasis. Of the 50 patients who underwent radical resection, 30 (60.0%) had clinically positive lymph nodes on the basis of the histopathology results. The optimal cutoff value for tumor size to predict cancer-specific survival was 1.5 cm. In patients with grade 2 rectal neuroendocrine tumors of ≤1.5-cm size, there were no significant differences in cancer-specific survival and relapse-free survival between local excision and radical resection groups ( p > 0.05). In patients with grade 2 rectal neuroendocrine tumors of >1.5-cm size, relapse-free survival was significantly lower in the local excision group than in the radical resection group ( p = 0.04). LIMITATIONS: The nature of retrospective reviews and a relatively short follow-up period are limitations of this study. CONCLUSIONS: Grade 2 rectal neuroendocrine tumors have a nonnegligible rate of lymph node metastasis. Local excision is a feasible choice for tumors of ≤1.5 cm size without metastasis, whereas radical resection is more beneficial in those of >1.5 cm size. See Video Abstract . ESCISIN LOCAL VERSUS RESECCIN RADICAL PARA TUMORES NEUROENDOCRINOS RECTALES GRADO ANLISIS MULTICNTRICO CON PUNTUACIN DE PROPENSIN COINCIDENTE: ANTECEDENTES:Los estudios sobre los tumores neuroendocrinos rectales de grado 2 son limitados y el tratamiento óptimo para estos tumores no está bien establecido.OBJETIVO:Comparar los resultados oncológicos de la escisión local versus la resección radical para el tratamiento de tumores neuroendocrinos rectales grado 2.DISEÑO:Estudio multicéntrico retrospectivo emparejado por puntuación de propensión para minimizar la heterogeneidad entre grupos y centrarse en la diferencia entre estrategias quirúrgicas.ESCENARIO:Diecisiete centros médicos chinos de gran tamaño participaron en este estudio.PACIENTES:Se analizaron retrospectivamente un total de 144 pacientes con tumores neuroendocrinos rectales grado 2 patológicamente confirmados.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron la supervivencia específica del cáncer y la supervivencia libre de recaída para comparar las estrategias quirúrgicas.RESULTADOS:En este estudio se inscribieron un total de 144 pacientes con tumores neuroendocrinos rectales grado 2. Veintisiete pacientes se sometieron a resección endoscópica, 55 a escisión transanal, 50 a resección radical y 12 a cirugía paliativa o biopsia por metástasis a distancia. De los 50 pacientes que se sometieron a resección radical, 30 (60,0%) tenían ganglios linfáticos clínicamente positivos según los resultados histopatológicos. El valor de corte óptimo para el tamaño del tumor para predecir la supervivencia específica del cáncer fue de 1,5 cm. En pacientes con tumores neuroendocrinos rectales grado 2 ≤ 1,5 cm, no hubo diferencias significativas en la supervivencia específica del cáncer y la supervivencia libre de recaída entre los grupos de escisión local y resección radical ( p >0,05). En pacientes con tumores neuroendocrinos rectales grado 2 > 1,5 cm, la supervivencia libre de recaída fue significativamente menor en el grupo de escisión local que en el grupo de resección radical ( p = 0,04).LIMITACIONES:La naturaleza de la revisión retrospectiva y el período de seguimiento relativamente corto son limitaciones de este estudio.CONCLUSIONES:Los tumores neuroendocrinos rectales grado 2 tienen una tasa no despreciable de metástasis en los ganglios linfáticos. La escisión local es una opción factible para tumores ≤ 1,5 cm sin metástasis, mientras que la resección radical es más beneficiosa en aquellos > 1,5 cm. (Traducción-Dr. Felipe Bellolio ).
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Tumores Neuroendocrinos , Puntaje de Propensión , Neoplasias del Recto , Humanos , Neoplasias del Recto/cirugía , Neoplasias del Recto/patología , Neoplasias del Recto/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/mortalidad , Estudios Retrospectivos , Anciano , Clasificación del Tumor , Proctectomía/métodos , Supervivencia sin Enfermedad , Adulto , Recurrencia Local de Neoplasia/epidemiología , Metástasis LinfáticaRESUMEN
Cancer immunotherapy is arguably the most rapidly advancing realm of cancer treatment. Glutathione peroxidase 4 (GPX4) has emerged as the vital enzyme to prevent lipid peroxidation and maintain cellular redox homeostasis. However, the mechanism of GPX4 in the regulation of cancer immunotherapy of colon adenocarcinoma (COAD) are incompletely understood. In pan-cancer analysis, we found that GPX4 showed remarkably upregulated expression and exhibited significant association with overall survival in multiple cancer types, especially COAD. Furthermore, upregulated GPX4 expression was positively correlated with increased immune cells infiltration and enhanced expression of immunomodulators. Mechanistically, RBM15B- and IGFBP2-mediated N6-methyladenosine (m6A) modification and NSUN5-mediated 5-methylcytosine (m5C) modification of GPX4 facilitated anticancer immunity via activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (STING) signaling by maintaining redox homeostasis in COAD. The risk model and nomogram model constructed based on the GPX4-derived genes further confirmed the prognostic and treatment-guiding value of GPX4. In all, our study demonstrated that m6A and m5C modification of GPX4 may be a promising target for cancer immunotherapy via activating the cGAS-STING signaling pathway in COAD.
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Adenocarcinoma , Neoplasias del Colon , Proteínas de la Membrana , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Humanos , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Nucleotidiltransferasas/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Proteínas de la Membrana/biosíntesisRESUMEN
Background: Although transverse colon ptosis (TCP) is commonly diagnosed in patients with constipation, it has not attracted significant attention in the evaluation of constipation. Herein, we assessed the correlation between TCP-related radiological parameters and the severity of slow transit constipation (STC). Methods: This study was a single-center retrospective cohort study, with participants enrolled between 2012 and 2020 in Zhongnan Hospital of Wuhan University, China. STC was diagnosed according to Rome IV criteria and results of colonic transit test (CTT); healthy volunteers were also recruited as controls. All participants were examined using abdominal X-rays (AXRs) to acquire the radiological parameters related to TCP. Among these parameters, the degree of TCP (DTCP) was defined as the vertical distance from the top of the splenic flexure to the lowest point of the reverse colon. The Wexner Constipation Score and Hospital Anxiety and Depression Scale were used to assess clinical severity. After multivariable linear regression, the correlations between radiological parameters and severity of STC were investigated. We also explored the differences in radiological parameters between the operation and the conservative group. Results: The study included 139 patients with STC and 125 healthy people in as the normal control (NC). Patients with STC probably had larger DTCPs than those in the NC group (242.27±25.86 vs. 93.00±32.57 mm; P<0.001). Pearson correlation analysis showed that TCP-related parameters were consistent with the symptom severity of STC [e.g., parameter DTCP was strongly correlated with Wexner Constipation Score, with a ß coefficient (95% CI) of 8.63 (8.24-9.02), P<0.001]. Multivariable linear regression models showed that patients with a larger DTCP were more likely to undergo surgery (23.67; 95% CI: 1.40-45.94; P=0.04). Conclusions: TCP-related parameters, especially the DTCP, may serve as novel and feasible alternative indices for the assessment of STC. However, the potential value of DTCP in assisting the evaluation of STC needs to be confirmed in study with a larger sample size.
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BACKGROUND: The prognostic nutritional index (PNI), alkaline phosphatase (ALP), and lymph node ratio (LNR) are reportedly related to prognosis. The aim of this study was to elucidate the clinical importance of the LNR and hematological parameters in patients with high grade rectal neuroendocrine neoplasms (HG-RNENs) who were undergoing radical resection. METHODS: We reviewed the medical records of patients with HG-RNENs from 17 large-scale medical centers in China (January 1, 2010-April 30, 2022). A nomogram was constructed by using a proportional hazard model. Bootstrap method was used to draw calibration plots to validate the reproducibility of the model. Concordance index (C-Index), decision curve analysis (DCA), and time-dependent area under the receiver operating characteristic curve (TD-AUC) analysis were used to compare the prognostic predictive power of the new model with American Joint Committee on Cancer (AJCC) TNM staging and European Neuroendocrine Tumor Society (ENETS) TNM staging. RESULTS: A total of 85 patients with HG-RNENs were enrolled in this study. In the 45 patients with HG-RNENs who underwent radical resection, PNI ≤ 49.13 (HR: 3.997, 95% CI: 1.379-11.581, P = 0.011), ALP > 100.0 U/L (HR: 3.051, 95% CI: 1.011-9.205, P = 0.048), and LNR > 0.40 (HR: 6.639, 95% CI: 2.224-19.817, P = 0.0007) were independent predictors of relapse-free survival. The calibration plots suggested that the nomogram constructed based on the three aforementioned factors had good reproducibility. The novel nomogram revealed a C-index superior to AJCC TNM staging (0.782 vs 0.712) and ENETS TNM staging (0.782 vs 0.657). Also, the new model performed better compared to AJCC TNM staging and ENETS TNM staging in DCA and TD-AUC analyses. CONCLUSIONS: LNR, ALP, and PNI were independent prognostic factors in patients with HG-RNENs after radical resection, and the combined indicator had better predictive efficacy compared with AJCC TNM staging and ENETS TNM staging.
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Índice Ganglionar , Tumores Neuroendocrinos , Humanos , Fosfatasa Alcalina , Enfermedad Crónica , Colorantes , Recurrencia Local de Neoplasia/cirugía , Tumores Neuroendocrinos/cirugía , Pronóstico , Reproducibilidad de los ResultadosRESUMEN
Evasion of antitumour immunity is a hallmark of cancer. STING, a putative innate immune signalling adaptor, has a pivotal role in mounting antitumour immunity by coordinating innate sensing and adaptive immune surveillance in myeloid cells. STING is markedly silenced in various human malignancies and acts as a cell-intrinsic tumour suppressor. How STING exerts intrinsic antitumour activity remains unclear. Here, we report that STING restricts aerobic glycolysis independent of its innate immune function. Mechanistically, STING targets hexokinase II (HK2) to block its hexokinase activity. As such, STING inhibits HK2 to restrict tumour aerobic glycolysis and promote antitumour immunity in vivo. In human colorectal carcinoma samples, lactate, which can be used as a surrogate for aerobic glycolysis, is negatively correlated with STING expression level and antitumour immunity. Taken together, this study reveals that STING functions as a cell-intrinsic metabolic checkpoint that restricts aerobic glycolysis to promote antitumour immunity. These findings have important implications for the development of STING-based therapeutic modalities to improve antitumour immunotherapy.
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Neoplasias Colorrectales , Hexoquinasa , Humanos , Hexoquinasa/genética , Hexoquinasa/metabolismo , Fosforilación , Transducción de Señal , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , GlucólisisRESUMEN
The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.
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Quinasas MAP Reguladas por Señal Extracelular , Receptor de Muerte Celular Programada 1 , Animales , Ratones , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismo , Homeostasis , InmunoterapiaRESUMEN
The metabolic pathways through which p53 functions as a potent tumor suppressor are incompletely understood. Here we report that, by associating with the Vitamin D receptor (VDR), p53 induces numerous genes encoding enzymes for peroxisomal fatty acid ß-oxidation (FAO). This leads to increased cytosolic acetyl-CoA levels and acetylation of the enzyme 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), which catalyzes the last two steps in the purine biosynthetic pathway. This acetylation step, mediated by lysine acetyltransferase 2B (KAT2B), occurs at ATIC Lys 266, dramatically inhibits ATIC activity, and inversely correlates with colorectal cancer (CRC) tumor growth in vitro and in vivo, and acetylation of ATIC is downregulated in human CRC samples. p53-deficient CRCs with high levels of ATIC is more susceptible to ATIC inhibition. Collectively, these findings link p53 to peroxisomal FAO, purine biosynthesis, and CRC pathogenesis in a manner that is regulated by the levels of ATIC acetylation.
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Transferasas de Hidroximetilo y Formilo , Proteína p53 Supresora de Tumor , Humanos , Purinas , Ácidos GrasosRESUMEN
Background: The RNA modification 5-methylcytosine (m5C) is one of the most prevalent post-transcriptional modifications, with increasing evidence demonstrating its extensive involvement in the tumorigenesis and progression of various cancers. Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related deaths worldwide. However, the role of m5C modulators in shaping tumor microenvironment (TME) heterogeneity and regulating immune cell infiltration in CRC requires further clarification. Results: The transcriptomic sequencing data of 18 m5C regulators and clinical data of patients with CRC were obtained from The Cancer Genome Atlas (TCGA) and systematically evaluated. We found that 16 m5C regulators were differentially expressed between CRC and normal tissues. Unsupervised cluster analysis was then performed and revealed two distinct m5C modification patterns that yielded different clinical prognoses and biological functions in CRC. We demonstrated that the m5C score constructed from eight m5C-related genes showed excellent prognostic performance, with a subsequent independent analysis confirming its predictive ability in the CRC cohort. Then we developed a nomogram containing five clinical risk factors and the m5C risk score and found that the m5C score exhibited high prognostic prediction accuracy and favorable clinical applicability. Moreover, the CRC patients with low m5C score were characterized by "hot" TME exhibiting increased immune cell infiltration and higher immune checkpoint expression. These characteristics were highlighted as potential identifiers of suitable candidates for anticancer immunotherapy. Although the high m5C score represented the non-inflammatory phenotype, the CRC patients in this group exhibited high level of sensitivity to molecular-targeted therapy. Conclusion: Our comprehensive analysis indicated that the novel m5C clusters and scoring system accurately reflected the distinct prognostic signature, clinicopathological characteristics, immunological phenotypes, and stratifying therapeutic opportunities of CRC. Our findings, therefore, offer valuable insights into factors that may be targeted in the development of precision medicine-based therapeutic strategies for CRC.
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Neoplasias Colorrectales , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Medicina de Precisión , Inmunoterapia , Terapia Molecular Dirigida , Neoplasias Colorrectales/genéticaRESUMEN
Background: RNA-binding proteins (RBPs) have important roles in orchestrating posttranscriptional regulation and modulating many tumorigenesis events. SERBP1 has been recognized as an important regulator in multiple cancers, while it remains unclear whether SERBP1-regulated gene expression at the transcriptome-wide level is significantly correlated with tumorigenesis. Methods: We overexpressed SERBP1 in HeLa cells and explored whether SERBP1 overexpression (SERBP1-OE) affects the proliferation and apoptosis of HeLa cells. We analyzed the transcriptome-wide gene expression changes and alternative splicing changes mediated by SERBP1-OE using the transcriptome sequencing method (RNA-seq). RT-qPCR was conducted to assay SERBP1-regulated alternative splicing. Results: SERBP1-OE induced the apoptosis of HeLa cells. The downregulated genes were strongly enriched in the cell proliferation and apoptosis pathways according to the GO analysis, including FOS, FOSB, PAK6 and RAB26. The genes undergoing at least one SERBP1-regulated alternative splicing event were enriched in transcriptional regulation, suggesting a mechanism of the regulation of gene expression, and in pyruvate and fatty acid metabolic processes critical for tumorigenesis events. The SERBP1-regulated alternative splicing of ME3, LPIN3, CROT, PDP1, SLC27A1 and ALKBH7 was validated by RT-qPCR analysis. Conclusions: We for the first time demonstrated the cellular function and molecular targets of SERBP1 in HeLa cells at transcriptional and post-transcriptional levels. The SERBP1-regulated gene expression and alternative splicing networks revealed by this study provide important information for exploring the functional roles and regulatory mechanisms of SERBP1 in cancer development and progression.
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Empalme Alternativo , Transcriptoma , Humanos , Empalme Alternativo/genética , Células HeLa , Proliferación Celular/genética , Carcinogénesis , Enzimas AlkB/genética , Proteínas Mitocondriales/genéticaRESUMEN
Bowel sounds is an important indicator to monitor and reflect intestinal motor function, and traditional manual auscultation requires high professional knowledge and rich clinical experience of doctors. In addition, long-time auscultation is time-consuming and laboriousï¼ which may lead to misjudgment caused by subjective error. To solve the problem, firstly, the wavelet transform is used to preprocess the bowel sounds signal for noise reduction and enhancement. Secondly, three typical features of intestinal sound were extracted. According to the combination of these features, a three-stage decision was designed to carry out multi-parameter and multi-feature joint threshold detection. This algorithm realized the detection of bowel sound signal and the location of its start and end points, making it possible that the complete bowel sound signal was extracted effectively. In this study, a large number of clinical data and label of bowel sounds were collected, and a new effective evaluation method was proposed to verify the proposed method. The accuracy rate is 83.51%. Results of this study will provide systematic support and theoretical guarantee for the diagnosis of intestinal diseases and the monitoring of postoperative intestinal function recovery of patients.
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Auscultación , Procesamiento de Señales Asistido por Computador , Algoritmos , Humanos , Intestinos , Análisis de OndículasRESUMEN
Circular RNAs (circRNAs) are a recently discovered kind of regulatory RNAs that have emerged as critical biomarkers of various types of cancers. Metabolic reprogramming has gradually been identified as a distinct hallmark of cancer cells. The pentose phosphate pathway (PPP) plays an indispensable role in satisfying the bioenergetic and biosynthetic demands of cancer cells. However, little is known about the role of circRNAs and PPP in colorectal cancer (CRC). The novel circ_0003215 was identified at low levels in CRC and was negatively correlated with larger tumor size, higher TNM stage, and lymph node metastasis. The decreased level of circ_0003215 was resulted from the RNA degradation by m6A writer protein YTHDF2. A series of functional assays demonstrated that circ_0003215 inhibited cell proliferation, migration, invasion, and CRC tumor metastasis in vivo and in vitro. Moreover, circ_0003215 regulated the expression of DLG4 via sponging miR-663b, thereby inducing the metabolic reprogramming in CRC. Mechanismly, DLG4 inhibited the PPP through the K48-linked ubiquitination of glucose-6-phosphate dehydrogenase (G6PD). Taken together, we have identified m6A-modified circ_0003215 as a novel regulator of metabolic glucose reprogramming that inhibited the PPP and the malignant phenotype of CRC via the miR-663b/DLG4/G6PD axis.
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Neoplasias Colorrectales , MicroARNs , Adenosina/análogos & derivados , Adenosina/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Homólogo 4 de la Proteína Discs Large/genética , Regulación Neoplásica de la Expresión Génica , Glucosa , Glucosafosfato Deshidrogenasa/genética , Glucosafosfato Deshidrogenasa/metabolismo , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Vía de Pentosa Fosfato/genética , ARN Circular/genéticaRESUMEN
Purpose: Increasing evidence has shown an association of surgical technique, particularly anastomotic configuration, with postoperative recurrence of CD. This pilot study aimed to evaluate short-term outcomes of isoperistaltic side-to-side anastomosis (ISSA) employed on Crohn disease (CD) patients. Methods: Data were retrieved from a prospectively maintained database. Postoperatively, all patients were followed up with close endoscopic (ileocolonoscopy) surveillance. Results: From January 2017 to May 2021, 30 patients diagnosed with CD who underwent ISSA were compared with 45 CD patients who underwent antiperistaltic side-to-side anastomosis (ASSA). The 2 groups were comparable in baseline demographics and clinical characteristics. No significant differences were observed between groups regarding postoperative safety issues, including anastomotic leak, abdominal/pelvic abscess, length of hospital stay, readmission rate within 30 days, etc. At postoperative 24th month, reduced endoscopic recurrence was observed in the ISSA group compared with that in the ASSA group (18 of 24, 75.0%, vs. 36 of 38, 94.7%; P = 0.024). Regarding surgical recurrence, there was 0% in the ISSA group vs. 4.4% (2 of 45) in the ASSA group (P = 0.510). Conclusion: In this study, we aimed to explore the influence of ISSA on postoperative recurrence in CD patients, and the preliminary results show that ISSA was technically safe and feasible, and appears to be effective in reducing postoperative recurrence in CD patients. However, our conclusion was underpowered due to small sample size and inadequate follow-up. We proposed ISSA be considered as another alternative option in the toolbox of inflammatory bowel disease surgeons when performing anastomosis on CD patients.