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BACKGROUND: Hematological and neurological expressed 1 (HN1) is upregulated in many tumors, but the role of HN1 in breast cancer progression and its regulatory mechanism have not been well understood. METHODS: To study the role of HN1 in the initiation and progression of breast cancer, we examined HN1 levels in breast cancer cells and tissues and analyzed the relationship between HN1 levels and patient survival. We used mammosphere formation assay, side population analysis, wound healing assay, transwell assay, soft agar formation assay, and xenografted tumor model to determine the effect of HN1 on the expansion of breast cancer stem cells, and the migration, invasion and tumorigenesis of breast cancer. To determine whether HN1 regulates MYC, we used quantitative real-time PCR and Western blot analysis to assess the expression of MYC and their targeted genes to determine the phenotype caused by knockdown of MYC in breast cancer cell with HN1 overexpression. RESULTS: In this study, we found that HN1 was upregulated in breast cancer tissues. Patients with high levels of HN1 expression had significantly shorter survival than those with low HN1 expression. In breast cancer cell line, ectopic overexpression of HN1 not only promoted the expansion of breast cancer stem cells, but also promoted cell migration, invasion, and tumorigenesis, while knockdown of HN1 reduced these effects. Furthermore, there was a positive correlation between MYC (also known as c-MYC) level and HN1 level, mechanism analysis suggested HN1 promoted the expression of MYC and its targeted genes like CDK4, CCND1, p21, CAV1, and SFRP1. Downregulation of MYC abrogated the effect of HN1 overexpression in breast cancer cell lines. CONCLUSION: Taken together, these data reveal that HN1 promotes the progression of breast cancer by upregulating MYC expression, and might be a therapeutic target for breast cancer.
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Neoplasias da Mama/genética , Carcinogênese/genética , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Camundongos , Proteínas Associadas aos Microtúbulos , Invasividade Neoplásica/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Breast cancer is one of the leading causes of death for women worldwide. Among various subtypes of breast cancer, human epidermal growth factor receptor 2 (HER2)-positive and phosphatase and tensin homolog (PTEN) loss breast cancer is a cause of great concern in terms of its resistance to HER2-targeted therapies and its poor prognosis. Phosphatidylinositol 3-kinase (PI3K)/AKT hyperphosphorylation is considered one of key mechanisms leading to this resistance, thus combination therapy of PI3K inhibitors and HER2 antibodies is promising for overcoming this problem, and more specific regimens should be designed in this age of precision medicine. In this study, we established an HER2-positive and PTEN loss cell line and confirmed it by western blot analysis. This cell line and its orthotopic xenograft models were exposed to p110α-specific inhibitor BYL719, p110ß-specific inhibitor AZD6482, or pan-PI3K inhibitor BKM120, respectively, and the results showed sensitivity to both BYL719 and BKM120 but not AZD6482, which indicated a p110α-reliance for HER2-positive-PTEN-loss breast cancer. Then, the addition of BYL719 to HER2 antibody greatly reduced tumor growth both in vitro and in vivo, accompanied by inhibited PI3K effector phosphorylation. Therefore, our findings suggest that the combination of p110α-selective inhibitor BYL719 with HER2 antibody could be a potential strategy for more personalized treatment of HER2-posistive-PTEN-loss breast cancer; and in addition, the optimal schedule of this combination therapy needs to be further explored.
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Neoplasias da Mama/tratamento farmacológico , PTEN Fosfo-Hidrolase/deficiência , Inibidores de Fosfoinositídeo-3 Quinase , Receptor ErbB-2/antagonistas & inibidores , Tiazóis/farmacologia , Aminopiridinas/farmacologia , Animais , Anticorpos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Lapatinib , Camundongos , Morfolinas/farmacologia , Fosforilação/efeitos dos fármacos , Pirimidinonas/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , ortoaminobenzoatos/farmacologiaRESUMO
Musical depth, which encompasses the intellectual and emotional complexity of music, is a robust dimension that influences music preference. However, there remains a dearth of research exploring the relationship between lyrics and musical depth. This study addressed this gap by analyzing linguistic inquiry and word count-based lyric features extracted from a comprehensive dataset of 2372 Chinese songs. Correlation analysis and machine learning techniques revealed compelling connections between musical depth and various lyric features, such as the usage frequency of emotion words, time words, and insight words. To further investigate these relationships, prediction models for musical depth were constructed using a combination of audio and lyric features as inputs. The results demonstrated that the random forest regressions (RFR) that integrated both audio and lyric features yielded superior prediction performance compared to those relying solely on lyric inputs. Notably, when assessing the feature importance to interpret the RFR models, it became evident that audio features played a decisive role in predicting musical depth. This finding highlights the paramount significance of melody over lyrics in effectively conveying the intricacies of musical depth.
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Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. Methods: We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR-mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon's minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Findings: Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. Interpretation: AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Funding: Chinese Thoracic Oncology Group (CTONG).
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To explore targeted treatment options in patients with non-small-cell lung cancer (NSCLC) with rare genetic mutations in the context of a patient-centric clinical trial, we initiated, in parallel, a phase 2 adaptive umbrella trial consisting of a criteria-fulfilled (CF) cohort and a compassionate use (CU) cohort under expanded eligibility criteria, and a prospective real-world study (RWS). Here, we present efficacy and safety data from 48 patients with treatment-naive, advanced HER2-mutant NSCLC treated with the pan-HER receptor tyrosine kinase inhibitor pyrotinib (CF and CU cohorts) or physician's therapy of choice (RWS cohort). In the phase 2 trial CF cohort (n = 28), the primary endpoint was reached with an objective response rate of 35.7% after pyrotinib treatment. Secondary endpoints included disease control rate (89.3%), median progression-free survival (PFS) (7.3 months), median overall survival (OS) (14.3 months) and toxicity, which was acceptable, with grade 3 or 4 treatment-related adverse events occurring in three patients (10.7%). The phase 2 trial CU cohort (n = 12) showed an objective response rate of 16.7%, disease control rate of 83.4%, median PFS of 4.7 months and median OS of 14.2 months after pyrotinib treatment. The RWS cohort (n = 8) had no responses to physician's therapy of choice, while median PFS and OS were 3.0 and 12.2 months, respectively. Phase 2 umbrella trial, clinicaltrials.gov identifier: NCT03574402 . RWS, clinicaltrials.gov identifier: NCT03605602 .
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Prospectivos , Assistência Centrada no PacienteRESUMO
BACKGROUND: Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples. METHOD: A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1PE-sDNA. RESULT: PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy. CONCLUSION: The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management.
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Carcinoma Pulmonar de Células não Pequenas/genética , Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/genética , Análise Mutacional de DNA/métodos , Neoplasias Pulmonares/genética , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Casos e Controles , Humanos , Biópsia Líquida , Neoplasias Pulmonares/patologia , Derrame PleuralRESUMO
OBJECTIVE: Leptomeningeal metastases (LM) occur in up to 5% of non-small cell lung cancer (NSCLC) patients and often develop after previous systemic treatments. In this article, we explored whether immune checkpoint inhibitors (ICIs) enhanced the dismal survival of patients with LM. MATERIALS AND METHODS: Data on NSCLC patients with LM prescribed ICIs were collected at the Guangdong Lung Cancer Institute. Furthermore, relevant literature was reviewed. RESULTS: A total of 255 NSCLC patients diagnosed with LM were screened from January 2015 to March 2020 at our institute. Cases reported by literature were also included. Finally, 32 NSCLC patients received ICIs after LM diagnosis; their median age was 55 years. Druggable genes were detected in 37.5% of all patients. The ICI regimens included nivolumab (n = 21), pembrolizumab (n = 9), and atezolizumab (n = 2). Ultimately, 62.5% of patients evidenced neurological symptom controlled. Two patients exhibited both intracranial and extracranial complete tumour response; one patient showed both intracranial and extracranial partial response (PR), one patient indicated intracranial PR and a systemic PR, and one patient showed central nervous system PR without extracranial response reported. The median progression-free survival (PFS) in the single-agent subgroup was 2.1 months (95% confidence interval [CI]: 1.4-2.9 months), and the median overall survival (OS) was 4.0 months (95% CI: 0.1-13.3 months). In the combined subgroup, the median PFS and OS were 3.0 months (95% CI: 1.1-4.9 months) and 5.4 months (95% CI: 0.5-10.3 months), respectively. Three patients exhibited remarkable PFS of over 20 months: all patients had ICI single agent, received cranial radiotherapy before ICI prescription, and took ICIs as second-line therapy, and two patients were EGFR/ALK wild type. Multivariate analysis showed that a better Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was associated with prolonged PFS (P = 0.04). No difference in survival was seen between monotherapy and combination therapy groups. CONCLUSION: NSCLC patients with LM may benefit from ICIs of both monotherapy and combination with other therapies, especially those with good ECOG-PS scores. Further work in this regard is required.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinomatose Meníngea/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Progressão da Doença , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Carcinomatose Meníngea/imunologia , Carcinomatose Meníngea/mortalidade , Carcinomatose Meníngea/secundário , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de TempoRESUMO
PURPOSE: Ferroptosis is a new mode of regulated cell death, which is completely distinct from other cell death modes based on morphological, biochemical, and genetic criteria. This study evaluated the therapeutic role of ferroptosis in classic chemotherapy drugs, including the underlying mechanism. MATERIALS AND METHODS: Cell viabilitywas detected by using the methylthiazoltetrazlium dye uptake method. RNAiwas used to knockout iron-responsive element binding protein 2, and polymerase chain reaction, western blot was used to evaluate the efficiency. Intracellular reduced glutathione level and glutathione peroxidases activitywere determined by related assay kit. Intracellularreactive oxygen species levelswere determined by flowcytometry. Electron microscopywas used to observe ultrastructure changes in cell. RESULTS: Among five chemotherapeutic drugs screened in this study, cisplatin was found to be an inducer for both ferroptosis and apoptosis in A549 and HCT116 cells. The depletion of reduced glutathione caused by cisplatin and the inactivation of glutathione peroxidase played the vital role in the underlying mechanism. Besides, combination therapy of cisplatin and erastin showed significant synergistic effect on their anti-tumor activity. CONCLUSION: Ferroptosis had great potential to become a new approach in anti-tumor therapies and make up for some classic drugs, which open up a new way for their utility in clinic.
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Cisplatino/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células A549 , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Morte Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/metabolismo , Fibrossarcoma/patologia , Glutationa Peroxidase/metabolismo , Células HCT116 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias/metabolismo , Piperazinas/metabolismoRESUMO
INTRODUCTION: Previous epidemiological studies have indicated an increased risk of breast cancer associated with digitalis medication, though results are inconsistent. We performed this systematic review of available epidemiological studies to clarify the association between digitalis use and the risk of breast cancer. METHODS: A search of studies published through May 2016 in MEDLINE and EMBASE databases was performed, supplemented by manual searches of reference lists. The quality of the included studies was assessed, and relative risks were pooled using both random- and fixed-effect models. RESULTS: Three case-control studies and six cohort studies were identified. Meta-analysis generated a pooled relative risk of 1.35 (95% confidence interval 1.24-1.46) in both fixed- and random-effect models. The heterogeneity test suggested low heterogeneity across studies. The funnel plot suggested no existence of publication bias. Subgroup analysis by study design revealed an increased risk of breast cancer associated with digitalis use from cohort studies only (relative risk = 1.39, 95% confidence interval 1.27-1.52), rather than from case-control studies. Studies with adjustment for tobacco smoking or body mass index generated lower overall estimates than those not adjusted. CONCLUSIONS: Existing epidemiological evidence regarding the association between digitalis use and the risk of breast cancer remains inconclusive and more well-designed studies are still needed.
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Neoplasias da Mama/etiologia , Cardiotônicos/efeitos adversos , Glicosídeos Digitálicos/efeitos adversos , Índice de Massa Corporal , Neoplasias da Mama/epidemiologia , Cardiotônicos/administração & dosagem , Glicosídeos Digitálicos/administração & dosagem , Feminino , Humanos , Modelos Estatísticos , Projetos de Pesquisa , Fatores de Risco , Fumar/epidemiologiaRESUMO
PURPOSE: In our previous study, we found that celecoxib, a kind of COX-2 inhibitor, led to cell apoptosis while up-regulating the expression of vascular endothelial growth factor (VEGF) in colorectal cancer HCT116 cells (COX-2 deficient), and endoplasmic reticulum (ER) stress was involved in the mechanism. Thus, we would like to explore whether these results are universal for other colorectal cancer cells, especially for COX-2-expressing ones, and whether the results in vitro and in vivo are matched. METHODS: HT29 cells (COX-2 expressing) were treated with celecoxib under different conditions to evaluate cell apoptosis, VEGF expression and the activation of ER stress. HT29 and HCT116 xenograft tumor models were established to evaluate anti-tumor effects and verify the experiment results we obtained in vitro. RESULTS: Celecoxib (≥60 µM) up-regulated the expression of ER stress markers (GRP78 and CHOP) and induced cell apoptosis accompanying with a correlated increased expression of VEGF in HT29 cells. Celecoxib-induced gene expression and cell apoptosis were inhibited by an ER stress inhibitor, PBA. In xenograft models, celecoxib treatment inhibited tumor growth with increased GRP78 and VEGF, which was consistent with the results in vitro. CONCLUSIONS: Celecoxib, both in vitro and in vivo, induced apoptosis of colorectal cancer cells but increased the VEGF levels at the same time in a COX-2-independent manner, namely by activating ER stress. The increased VEGF would impair the effect of celecoxib and bring drug resistant; hence, the optimal schedule of the combination of celecoxib with anti-VEGF drugs needs to be explored.