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Colorectal cancer (CRC) is a prevalent form of gastrointestinal malignancy with challenges in chemotherapy resistance and side effects. Effective and low toxic drugs for CRC treatment are urgently needed. Ferroptosis is a novel mode of cell death, which has garnered attention for its therapeutic potential against cancer. Baicalein (5, 6, 7-trihydroxyflavone) is the primary flavone extracted from the dried roots of Scutellaria baicalensis that exhibits anticancer effects against several malignancies including CRC. In this study, we investigated whether baicalein induced ferroptosis in CRC cells. We showed that baicalein (1-64 µM) dose-dependently inhibited the viability of human CRC lines HCT116 and DLD1. Co-treatment with the ferroptosis inhibitor liproxstatin-1 (1 µM) significantly mitigated baicalein-induced CRC cell death, whereas autophagy inhibitor chloroquine (25 µM), necroptosis inhibitor necrostatin-1 (10 µM), or pan-caspase inhibitor Z-VAD-FMK (10 µM) did not rescue baicalein-induced CRC cell death. RNA-seq analysis confirmed that the inhibitory effect of baicalein on CRC cells is associated with ferroptosis induction. We revealed that baicalein (7.5-30 µM) dose-dependently decreased the expression levels of GPX4, key regulator of ferroptosis, in HCT116 and DLD1 cells by blocking janus kinase 2 (JAK2)/STAT3 signaling pathway via direct interaction with JAK2, ultimately leading to ferroptosis in CRC cells. In a CRC xenograft mouse model, administration of baicalein (10, 20 mg/kg, i.g., every two days for two weeks) dose-dependently inhibited the tumor growth with significant ferroptosis induced by inhibiting the JAK2/STAT3/GPX4 axis in tumor tissue. This study demonstrates that ferroptosis contributes to baicalein-induced anti-CRC activity through blockade of the JAK2/STAT3/GPX4 signaling pathway, which provides evidence for the therapeutic application of baicalein against CRC.
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Neoplasias Colorrectales , Ferroptosis , Flavanonas , Janus Quinasa 2 , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Factor de Transcripción STAT3 , Flavanonas/farmacología , Flavanonas/uso terapéutico , Humanos , Ferroptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Animales , Janus Quinasa 2/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Ratones , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/antagonistas & inhibidores , Ratones Desnudos , Ratones Endogámicos BALB C , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Células HCT116 , Ensayos Antitumor por Modelo de Xenoinjerto , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a DrogaRESUMEN
Background: Patients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear. Methods: A total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue samples were performed by targeted DNA sequencing, and 21 cases were performed by NanoString immuno-oncology targeted RNA sequencing to identify the distinct molecular bases and immunologic features associated with relapse in patients with early laryngeal cancer, respectively. Results: To the best to our knowledge, we present for the first time an overview of the genomic mutation spectrum of early-stage laryngeal cancers. A total of 469 genomic alterations were detected in 211 distinct cancer-relevant genes, and the genes found to be mutated in more than five patients (>10%) included tumor protein p53 (TP53, 78.5%), FAT atypical cadherin 1 (FAT1, 26%), LDL receptor related protein 1B (LRP1B, 19%), cyclin dependent kinase inhibitor 2A (CDKN2A, 17%), tet methylcytosine dioxygenase 2 (TET2, 17%), notch receptor 1 (NOTCH1, 12%) and neuregulin 1 (NRG1, 12%). Recurrent laryngeal cancer demonstrated a higher tumor mutation burden (TMB), as well as higher LRP1B mutation and NOTCH1 mutation rates. Univariate and multivariate analyses revealed that high TMB (TMB-H) and NOTCH1 mutation are independent genetic factors that are significantly associated with shorter relapse-free survival (RFS). Simultaneously, the results of the transcriptome analysis presented recurrent tumors with NOTCH1 mutation displayed upregulation of the cell cycle pathway, along with decreased B cells score, T cells score, immune signature score and tumor-infiltrating lymphocytes (TILs) score. The Cancer Genome Atlas (TCGA)-laryngeal cancer dataset also revealed weakened immune response and impaired adhesion functions in NOTCH1-mutant patients. Conclusions: Genomic instability and impaired immune response are key features of the immunosurveillance escape and recurrence of early laryngeal cancer after surgery. These findings revealed immunophenotypic attenuation in recurrent tumors and provided valuable information for improving the management of these high-risk patients. Due to the small number of patients in this study, these differences need to be further validated in a larger cohort.
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Neoplasias Laríngeas , Receptor Notch1 , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Humanos , Inmunidad/genética , Neoplasias Laríngeas/complicaciones , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/cirugía , Mutación , Recurrencia Local de Neoplasia/patología , Receptor Notch1/genética , Receptor Notch1/inmunologíaRESUMEN
Novel adjuvant strategies are needed to optimize outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). The adjuvant treatment of ROS Proto-Oncogene 1 (ROS1) fusion-positive resected NSCLC is challenging because there is no curative confirmed randomized controlled trial. Next-generation sequencing (NGS) and immunohistochemistry (IHC) staining were performed on the biopsy sample. In this case, we identified a novel LDLR-ROS1 fusion in a resectable stage IIIA NSCLC patient. The patient received crizotinib as adjuvant treatment and achieved recurrence-free survival (RFS) for 29 months, without significant symptoms of toxicity. In this case, we report a novel LDLR-ROS1 fusion responding to crizotinib in a patient with lung adenocarcinoma, supporting the use of adjuvant treatment with the ROS1 inhibitor exerting clinical survival benefit in ROS1 fusion-positive resected NSCLC.
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BACKGROUND: Sarcomatoid carcinoma (SC) of the head and neck (HN) is a rare disease that has both sarcomatoid and cancerous components. The genetic background and mechanisms of tumorigenesis remain largely unrevealed, and the progress of precision therapy has been limited. METHODS: Targeted DNA-based next-generation sequencing (NGS) was performed by a 539 genes panel of pan-cancer in 12 patients with SC of the HN to identify their genetic alterations and investigate clinically actionable mutations for use in precision treatment. RESULTS: TP53 was identified as the most frequently mutated gene. Genes related to the cell cycling, chromatin remodeling and histone modification were found to be frequently mutated in patients with SC of the HN. Alterations in receptor tyrosine kinases (RTKs) were also found in six patients. In addition, four patients had mutations in members of the downstream RAS and PI3-kinase pathways, PIK3CA was identified as the most frequently mutated gene in this pathway. The tumor mutation burden (TMB) value ranged from 0.71 to 14.71 per megabase, with a median of 4.34. The TMB value of PIK3CA mutation patients was significantly higher than that of PIK3CA wild-type patients. CONCLUSIONS: This was the first study to investigate genomic alterations specifically in Chinese patients with SC of the HN. Our research results showed that 10 out of 12 patients can match the targeted therapies or immunotherapy currently available in clinical practice or active clinical trials, suggesting precision therapy has the potential utility to improve the long-term prognosis for patients with the rare disease. Due to the small number of patients in this study, the findings need to be validated in a larger cohort.
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Carcinoma , Neoplasias de Cabeza y Cuello/genética , Biomarcadores de Tumor , Carcinoma/genética , China , Fosfatidilinositol 3-Quinasa Clase I/genética , Análisis Mutacional de ADN , Genómica , Humanos , Mutación , Enfermedades RarasRESUMEN
The red water in the drinking distribution systems of a southern city was investigated by analysing the water quality, such as DO, residual chlorine, iron, manganese, iron bacteria and ammonia-oxidizing bacteria. The objectives of this study were to identify the reasons of red water with the aim to supply the answer to this problem. The results showed that the main compositions of the deposits were iron and manganese. There were manganese overstep (the maximum of Mn could reach to 0.33 mg x L(-1)) in the plant effluent with Larson ratios > 1 and the significant difference in water quantity, sulfate and electrical conductivity among the four plants. The density of the iron bacteria and ammonia-oxidizing bacteria (10(0)-10(3) MPN x mL(-1)) was high. The potential reason for the red water was the water corrosion of plant effluent. Secondly, the red water easily occurred in the distribution systems with lower DO and residual chlorine. In addition, serious nitrification caused microbiological corrosion was another vital reason. According to the research, the primary methods for controlling red water were proposed.