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BACKGROUND: Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS: In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS: Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS: This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY: To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.
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Neoplasias , Trombocitopenia , Humanos , China , Estudios Transversales , Interleucina-11/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Trombopoyetina/uso terapéutico , Adulto Joven , AdultoRESUMEN
BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment. FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Letrozol , Anastrozol , Resultado del Tratamiento , Supervivencia sin Enfermedad , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Método Doble CiegoRESUMEN
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) targeted therapy combined with endocrine therapy has been recommended as an alternative treatment strategy for patients with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (MBC). This study aimed to evaluate the role of pyrotinib, an oral pan-HER irreversible tyrosine kinase inhibitor, in combination with letrozole for patients with HR-positive, HER2-positive MBC. METHODS: In this multi-center, phase II trial, HR-positive and HER2-positive MBC patients who were not previously treated for metastasis disease were enrolled. Patients received daily oral pyrotinib 400 mg and letrozole 2.5 mg until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the clinical benefit rate (CBR) assessed by an investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: From November 2019 to December 2021, 53 patients were enrolled and received pyrotinib plus letrozole. As of August 2022, the median follow-up duration was 11.6 months (95% confidence interval [CI], 8.7-14.0 months). The CBR was 71.7% (95% CI, 57.7-83.2%), and the objective response rate was 64.2% (95% CI, 49.8-76.9%). The median progression-free survival was 13.7 months (95% CI, 10.7-18.7 months). The most common treatment-related adverse event of grade 3 or higher was diarrhea (18.9%). No treatment-related deaths were reported, and one patient experienced treatment discontinuation due to adverse event. CONCLUSIONS: Our preliminary results suggested that pyrotinib plus letrozole is feasible for the first-line treatment of patients with HR-positive and HER2-positive MBC, with manageable toxicities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04407988.
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Neoplasias de la Mama , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Letrozol/uso terapéutico , Receptor ErbB-2 , Resultado del TratamientoRESUMEN
Importance: The bioequivalence of denosumab biosimilar has yet to be studied in a 53-week, multicenter, large-scale, and head-to-head trial. A clinically effective biosimilar may help increase access to denosumab in patients with solid tumor-related bone metastases. Objectives: To establish the biosimilarity of MW032 to denosumab in patients with solid tumor-related bone metastases based on a large-scale head-to-head study. Design, Setting, and Participants: In this 53-week, randomized, double-blind, phase 3 equivalence trial, patients with solid tumors with bone metastasis were recruited from 46 clinical sites in China. Overall, 856 patients were screened and 708 eligible patients were randomly allocated to receive either MW032 or denosumab. Interventions: Patients were randomly assigned (1:1) to receive MW032 or reference denosumab subcutaneously every 4 weeks until week 49. Main Outcomes and Measures: The primary end point was percentage change from baseline to week 13 of natural logarithmic transformed urinary N-telopeptide/creatinine ratio (uNTx/uCr). Results: Among the 701 evaluable patients (350 in the MW032 group and 351 in the denosumab group), the mean (range) age was 56.1 (22.0-86.0) years and 460 patients were women (65.6%). The mean change of uNTx/uCr from baseline to week 13 was -72.0% (95% CI, -73.5% to -70.4%) in the MW032 group and -72.7% (95% CI, -74.2% to -71.2%) in the denosumab group. These percent changes corresponded to mean logarithmic ratios of -1.27 and -1.30, or a difference of 0.02. The 90% CI for the difference (-0.04 to 0.09) was within the equivalence margin (-0.13 to 0.13); the mean changes of uNTx/uCr and bone-specific alkaline phosphatase (s-BALP) at each time point were also similar during 53 weeks. The differences of uNTx/uCr change were 0.015 (95% CI, -0.06 to 0.09), -0.02 (95% CI, -0.09 to 0.06), -0.05 (95% CI, -0.13 to 0.03) and 0.001 (95% CI, -0.10 to 0.10) at weeks 5, 25, 37, and 53, respectively. The differences of s-BALP change were -0.006 (95% CI, 0.06 to 0.05), 0.00 (95% CI, -0.07 to 0.07), -0.085 (95% CI, -0.18 to 0.01), -0.09 (95% CI, -0.20 to 0.02), and -0.13 (95% CI, -0.27 to 0.004) at weeks 5, 13, 25, 37 and 53, respectively. No significant differences were observed in the incidence of skeletal-related events (-1.4%; 95% CI, -5.8% to 3.0%) or time to first on-study skeletal-related events (unadjusted HR, 0.86; P = .53; multiplicity adjusted HR, 0.87; P = .55) in the 2 groups. Conclusions and Relevance: MW032 and denosumab were biosimilar in efficacy, population pharmacokinetics, and safety profile. Availability of denosumab biosimilars may broaden the access to denosumab and reduce the drug burden for patients with advanced tumors. Trial Registration: ClinicalTrials.gov Identifier: NCT04812509.
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Biosimilares Farmacéuticos , Neoplasias Óseas , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Denosumab , Anticuerpos Monoclonales Humanizados , Neoplasias Óseas/secundario , Creatinina , Método Doble CiegoRESUMEN
RATIONALE: Male secretory breast cancer is a rare, low-grade carcinoma, especially in boys. Due to its rarity, not much is known about this disease. PATIENT CONCERNS: A 5-year-old boy presented with a 1.4 cm painless mass in the right breast. DIAGNOSES: Ultrasonography could not distinguish whether the breast tumor was benign or malignant. After a biopsy of the lumpectomy specimen, it was diagnosed to be secretory breast carcinoma. INTERVENTIONS: The patient underwent a modified radical mastectomy for his right breast. No postoperative chemotherapy or radiotherapy was performed. Next-generation sequencing of 211 cancer-related genes was detected, and the results revealed an ETV6-NTRK3 translocation and a PDGFRB c.2632Aâ >â G mutation. None of the most commonly altered molecules in male aggressive breast cancer (such as BRCA1-2, TP53, RAD51C, and RAD51D mutations) has been identified. OUTCOMES: The patient was still free from local recurrence or metastases at 6-month follow-up. LESSONS: The genomic profile of male pediatric SCB is relatively simple, no other known driver genes have been found except for the ETV6-NTRK3 fusion. Our report will improve our understanding of secretory breast cancer.
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Neoplasias de la Mama Masculina , Neoplasias de la Mama , Humanos , Masculino , Niño , Preescolar , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteínas de Fusión Oncogénica/genética , Mastectomía , Neoplasias de la Mama Masculina/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Biomarcadores de Tumor/genéticaRESUMEN
OBJECTIVE: To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel for untreated HER2 positive metastatic breast cancer. DESIGN: Randomised, double blind, placebo controlled, multicentre, phase 3 trial. SETTING: 40 centres in China between 6 May 2019 and 17 January 2022. PARTICIPANTS: 590 female patients (median age 52 (interquartile range 46-58) years) with untreated HER2 positive metastatic breast cancer. INTERVENTIONS: Eligible patients were randomised 1:1 to receive either oral pyrotinib (400 mg once daily) or placebo, both combined with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m2) on day 1 of each 21 day cycle. Randomisation was stratified by treatment history of trastuzumab in the (neo)adjuvant setting and hormone receptor status. Patients, investigators, and the sponsor's study team were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival as assessed by the investigator. RESULTS: Of the 590 randomised patients, 297 received pyrotinib, trastuzumab, and docetaxel treatment (pyrotinib group), and 293 received placebo, trastuzumab, and docetaxel treatment (placebo group). At data cut-off on 25 May 2022, the median follow-up was 15.5 months. The median progression-free survival according to the investigator was significantly longer in the pyrotinib group than in the placebo group (24.3 (95% confidence interval 19.1 to 33.0) months versus 10.4 (9.3 to 12.3) months; hazard ratio 0.41 (95% confidence interval 0.32 to 0.53); one sided P<0.001). Treatment related adverse events of grade 3 or higher were reported in 267 (90%) of the 297 patients in the pyrotinib group and 224 (76%) of the 293 patients in the placebo group. No treatment related deaths occurred in the pyrotinib group, and one (<1%; diabetic hyperosmolar coma) treatment related death occurred in the placebo group. Survival and toxicities are still under assessment with longer follow-up. CONCLUSIONS: Pyrotinib, trastuzumab, and docetaxel showed superiority by significantly improving progression-free survival compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2 positive metastatic breast cancer. The toxicity was manageable. The findings support this dual anti-HER2 regimen as an alternative first line treatment option in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03863223.
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Neoplasias de la Mama , Femenino , Humanos , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Docetaxel/efectos adversos , Docetaxel/uso terapéutico , Método Doble Ciego , Receptor ErbB-2/metabolismo , Trastuzumab/efectos adversos , Trastuzumab/uso terapéutico , Resultado del TratamientoRESUMEN
Background: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer and lacks effective biomarkers. This study seeks to unravel the expression status and the prospective transcriptional mechanisms of EZH1/EZH2 in TNBC tissue samples. Moreover, another objective of this study is to reveal the prognostic molecular signatures for risk stratification in TNBC patients. Methods: To determine the expression status of EZH1/EZH2 in TNBC tissue samples, microarray analysis and immunohistochemistry were performed on in house breast cancer tissue samples. External mRNA expression matrices were used to verify its expression patterns. Furthermore, the prospective transcriptional mechanisms of EZH1/EZH2 in TNBC were explored by performing differential expression analysis, co-expression analysis, and chromatin immunoprecipitation sequencing analysis. Kaplan-Meier survival analysis and univariate Cox regression analysis were utilized to detect the prognostic molecular signatures in TNBC patients. Nomogram and time-dependent receiver operating characteristic curves were plotted to predict the risk stratification ability of the prognostic-signatures-based Cox model. Results: In-house TMAs (66 TNBC vs. 106 non-TNBC) and external gene microarrays, as well as RNA-seq datasets (1,135 TNBC vs. 6,198 non-TNBC) results, confirmed the downregulation of EZH1 at both the protein and mRNA levels (SMD = -0.59 [-0.80, -0.37]), as is opposite to that of EZH2 (SMD = 0.74 [0.40, 1.08]). The upregulated transcriptional target genes of EZH1 were significantly aggregated in the cell cycle pathway, where CCNA2, CCNB1, MAD2L1, and PKMYT1 were determined as key transcriptional targets. Additionally, the downregulated transcriptional targets of EZH2 were enriched in response to the hormone, where ESR1 was identified as the hub gene. The six-signature-based prognostic model produced an impressive performance in this study, with a training AUC of 0.753, 0.981, and 0.977 at 3-, 5-, and 10-year survival probability, respectively. Conclusion: EZH1 downregulation may be a key modulator in the progression of TNBC through negative transcriptional regulation by targeting CCNA2, CCNB1, MAD2L1, and PKMYT1.
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Neoplasias de la Mama Triple Negativas , Humanos , Proteínas de Ciclo Celular/genética , Regulación hacia Abajo/genética , Proteínas de la Membrana/genética , Pronóstico , Estudios Prospectivos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , ARN Mensajero , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
ABSTRACT: This study aimed to investigate the prognostic factors of patients after liver cancer surgery and evaluate the predictive power of nomogram. Liver cancer patients with the history of surgery in the Surveillance, Epidemiology, and End Results database between 2000 and 2016 were preliminary retrieved. Patients were divided into the survival group (nâ=â2120, survival ≥5âyears) and the death group (nâ=â2615, survivalâ<â5âyears). Single-factor and multi-factor Cox regression were used for analyzing the risk factors of death in patients with liver cancer after surgery. Compared with single patients, married status was the protective factor for death in patients undergoing liver cancer surgery (HRâ=â0.757, 95%CI: 0.685-0.837, Pâ<â.001); the risk of death in Afro-Americans (HRâ=â1.300, 95%CI: 1.166-1.449, Pâ<â.001) was higher than that in Caucasians, while the occurrence of death in Asians (HRâ=â0.821, 95%CI: 0.1754-0.895, Pâ<â.0012) was lower; female patients had a lower incidence of death (HRâ=â0.875, 95%CI: 0.809-0.947, Pâ<â.001); grade II (HRâ=â1.167, 95%CI: 1.080-1.262, Pâ<â.001), III (HRâ=â1.580, 95%CI: 1.433-1.744, Pâ<â.001), and IV (HRâ=â1.419, 95%CI: 1.145-1.758, Pâ=â0.001) were the risk factors for death in patients with liver cancer. The prognostic factors of liver cancer patients after surgery include the marital status, race, gender, age, grade of cancer and tumor size. The nomogram with good predictive ability can provide the prediction of 5-year survival for clinical development.
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Neoplasias Hepáticas/cirugía , Pronóstico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Programa de VERF/estadística & datos numéricos , Análisis de SupervivenciaRESUMEN
Immune-related genes (IRGs) are closely related to tumor progression and the immune microenvironment. Few studies have investigated the effect of tumor immune microenvironment on the survival and response to immune checkpoint inhibitors of patients with bladder urothelial carcinoma (BLCA). We constructed two IRG-related prognostic signatures based on gene-immune interaction for predicting risk stratification and immunotherapeutic responses. We also verified their predictive ability on internal and overall data sets. Patients with BLCA were divided into high- and low-risk groups. The high-risk group had poor survival, enriched innate immune-related cell subtypes, low tumor mutation burden, and poor response to anti-PD-L1 therapy. Our prognostic signatures can be used as reliable prognostic biomarkers, which may be helpful to screen the people who will benefit from immunotherapy and guide the clinical decision-making of patients with BLCA.
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SAC3 domain containing 1 (SAC3D1) has been reported to be involved in numerous types of cancer. However, the role of SAC3D1 in GC has not yet been elucidated. In the present study, the mRNA expression level of SAC3D1 between GC and normal tissues were assessed with a continuous variable metaanalysis based on multiple datasets from public databases. The protein expression level of SAC3D1 in GC and normal tissues was assessed by an inhouse immunohistochemistry (IHC). The association between SAC3D1 expression and some clinical parameters was assessed based on the TCGA and IHC data. Survival analysis was performed to assess the association between SAC3D1 expression and the survival of GC patients. The coexpressed genes of SAC3D1 were determined by integrating three online tools, and the enrichment analyses were performed to determine SAC3D1related pathways and hub coexpressed genes. SAC3D1 was significantly upregulated in GC tumor tissues in comparison to normal tissues with the SMD being 0.45 (0.12, 0.79). The IHC results also indicated that SAC3D1 protein expression in GC tissues was markedly higher than in normal tissues. The SMD following the addition of the IHC data was 0.59 (0.11, 1.07). The protein levels of SAC3D1 were positively associated with the histological grade, T stage and N stage of GC (P<0.001). The TCGA data also revealed that the SAC3D1 mRNA level was significantly associated with the N stage (P<0.001). Moreover, prognosis analysis indicated that SAC3D1 was closely associated with the prognosis of patients with GC. Moreover, 410 coexpressed genes of SAC3D1 were determined, and these genes were mainly enriched in the cell cycle. In total, 4 genes (CDK1, CCNB1, CCNB2 and CDC20) were considered key coexpressed genes. On the whole, these findings demonstrate that SAC3D1 is highly expressed in GC and may be associated with the progression of GC.
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Biomarcadores de Tumor/metabolismo , Proteínas Represoras/metabolismo , Neoplasias Gástricas/diagnóstico , Estómago/patología , Biomarcadores de Tumor/análisis , Biología Computacional , Conjuntos de Datos como Asunto , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , RNA-Seq , Proteínas Represoras/análisis , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Supervivencia , Regulación hacia ArribaRESUMEN
Alternative splicing can lead to the coding of proteins that act as promoters of cancer, which is associated with the progression of cancer. However, to the best of our knowledge, no systematic survival analysis of alternative splicing in melanoma has previously been reported. The present study conducted an in-depth analysis of integrated alternative splicing events detected in 96 patients with melanoma using data obtained from The Cancer Genome Atlas. Prognostic models and an alternative splicing correlation network were built for patients with melanoma. A total of 41,446 mRNA splicing events were detected in 9,780 genes and 2,348 alternative splicing events were identified to be significantly associated with overall survival of patients with melanoma. Of all the events used in the prognostic model, the model with alternate terminator alternative splicing events exhibited the highest efficiency for evaluating the outcome of patients with melanoma, with an area under the curve of 0.902. The present study identified prognostic predictors for melanoma and revealed alternative splicing networks in melanoma that could indicate underlying mechanisms.
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Esophageal squamous cell carcinoma (ESCC) accounts for over 90% of all esophageal tumors. However, the molecular mechanism underlying ESCC development and prognosis remains unclear, and there are still no effective molecular biomarkers for diagnosing or predicting the clinical outcome of patients with ESCC. Here, using bioinformatics analyses, we attempted to identify potential biomarkers and therapeutic targets for ESCC. Differentially expressed genes (DEGs) between ESCC and normal esophageal tissue samples were obtained through comprehensive analysis of three publicly available gene expression profile datasets from the Gene Expression Omnibus database. The biological roles of the DEGs were identified by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Moreover, the Cytoscape 3.7.1 platform and subsidiary tools such as Molecular Complex Detection (MCODE) and CytoHubba were used to visualize the protein-protein interaction (PPI) network of the DEGs and identify hub genes. A total of 345 DEGs were identified between normal esophageal and ESCC samples, which were enriched in the KEGG pathways of the cell cycle, endocytosis, pancreatic secretion, and fatty acid metabolism. Two of the highest scoring models were selected from the PPI network using Molecular Complex Detection. Moreover, CytoHubba revealed 21 hub genes with a valuable influence on the progression of ESCC in these patients. Among these, the high expression levels of five genes-SPP1, SPARC, BGN, POSTN, and COL1A2-were associated with poor disease-free survival of ESCC patients, as indicated by survival analysis. Taken together, we identified that elevated expression of five hub genes, including SPP1, is associated with poor prognosis in ESCC patients, which may serve as potential prognostic biomarkers or therapeutic target for ESCC.
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Biología Computacional , Carcinoma de Células Escamosas de Esófago/genética , Proteínas de Neoplasias/genética , Pronóstico , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas de Esófago/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Ontología de Genes , Redes Reguladoras de Genes/genética , Humanos , Análisis por Micromatrices , Mapas de Interacción de Proteínas/genéticaRESUMEN
Several studies have indicated that microRNAs (miRs) mediate multiple pathways associated with tumorigenesis and progression. Our preliminary study experimentally verified that miR146a5p has a role in the biological behavior of nonsmall cell lung cancer (NSCLC) cells. To perform further investigation of miR146a5p, the present study evaluated miR146a5p by targeting its downstream gene tumor collagenase stimulatory factor (TCSF) to influence cell viability, proliferation and apoptosis in NSCLC. Online sequence prediction, a thorough search of the open source database The Cancer Genome Atlas (TCGA), immunohistochemistry (IHC) of TCSF in clinical lung cancer tissues, and a dualluciferase assay, as well as assays to test viability, proliferation and apoptosis in vitro, were conducted to explain the targeted regulation association between miR146a5p and TCSF in NSCLC. The miRanda and TargetScanHuman database revealed that TCSF and miR146a5p had target binding sites. A luciferase reporter assay demonstrated that miR146a5p and TCSF did have complementary sequences (P<0.05). From the TCGA database, TCSF was highly expressed in lung adenocarcinoma and lung squamous cell carcinoma tissues when compared with normal lung tissues (P<0.05). Furthermore, the protein level of TCSF in cancerous lung tissues was determined by IHC, and it was concluded that TCSF protein was also upregulated in NSCLC tissues (P<0.001). A significant difference was identified following in vitro experiments for the NSCLC cell line A549, which revealed that miR146a5p and TCSF regulated cell viability, proliferation and apoptosis. In conclusion, the present study verified the target action association between TCSF and miR146a5p with high throughput data analysis and experimental results in NSCLC.
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Basigina/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , MicroARNs/metabolismo , Células A549 , Adulto , Anciano , Apoptosis/genética , Basigina/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/genética , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Femenino , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , ARN Interferente Pequeño/metabolismoRESUMEN
Breast cancer (BC) is the most common cancer among women worldwide. However, there is insufficient research that focuses on the expression and molecular mechanisms of microRNA (miR)2045p in BC. In the current study, data were downloaded from the Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO) and the University of California Santa Cruz (UCSC) Xena databases. They were then used to undertake a metaanalysis that leveraged the standard mean difference (SMD) and summarized receiver operating characteristic (sROC) to evaluate the expression of the precursor miR204 and mature miR2045p in BC. Additionally, an intersection of predicted genes, differentially expressed genes (DEGs) from the TCGA database and the GEO database were plotted to acquire desirable putative genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and proteinprotein interaction (PPI) network analyses were performed to assess the potential pathways and hub genes of miR2045p in BC. A decreased trend in precursor miR204 expression was detected in 1,077 BC tissue samples in comparison to 104 paracarcinoma tissue samples in the TCGA database. Further, the expression of mature miR2045p was markedly downregulated in 756 BC tissue samples in comparison to 76 paracarcinoma tissue samples in the UCSC Xena database. The outcome of the SMD from metaanalysis also indicated that the expression of miR2045p was markedly reduced in 2,306 BC tissue samples in comparison to 367 paracarcinoma tissue samples. Additionally, the ROC and sROC values indicated that miR2045p had a great discriminatory capacity for BC. In GO analysis, 'cell development', 'cell surface activity', and 'receptor agonist activity' were the most enriched terms; in KEGG analysis, 'endocytosis' was significantly enriched. Rac GTPase activating protein 1 (RACGAP1) was considered the hub gene in the PPI network. In conclusion, miR2045p may serve a suppressor role in the oncogenesis and advancement of BC, and miR2045p may have crucial functions in BC by targeting RACGAP1.
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Neoplasias de la Mama/genética , MicroARNs/genética , Biomarcadores de Tumor/genética , Biología Computacional/métodos , Regulación hacia Abajo/genética , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Ontología de Genes , Humanos , Mapas de Interacción de Proteínas/genética , Curva ROC , Transducción de Señal/genéticaRESUMEN
Cinobufotalin is a chemical compound extracted from the skin of dried bufo toads that may have curative potential for certain malignancies through different mechanisms; however, these mechanisms remain unexplored in breast cancer. The aim of the present study was to investigate the antitumor mechanism of cinobufotalin in breast cancer by using microarray data and in silico analysis. The microarray data set GSE85871, in which cinobufotalin exerted influences on the MCF7 breast cancer cells, was acquired from the Gene Expression Omnibus database, and the differentially expressed genes (DEGs) were analyzed. Subsequently, protein interaction analysis was conducted, which clarified the clinical significance of core genes, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to analyze cinobufotalinrelated pathways. The Connectivity Map (CMAP) database was used to select existing compounds that exhibited curative properties similar to those of cinobufotalin. A total of 1,237 DEGs were identified from breast cancer cells that were treated with cinobufotalin. Two core genes, SRC protooncogene nonreceptor tyrosine kinase and cyclindependent kinase inhibitor 2A, were identified as serving a vital role in the onset and development of breast cancer, and their expression levels were markedly reduced following cinobufotalin treatment as detected by the microarray of GSE85871. It also was revealed that the 'neuroactive ligandreceptor interaction' and 'calcium signaling' pathways may be crucial for cinobufotalin to perform its functions in breast cancer. Conducting a matching search in CMAP, miconazole and cinobufotalin were indicated to possessed similar molecular mechanisms. In conclusion, cinobufotalin may serve as an effective compound for the treatment of a subtype of breast cancer that is triple positive for the presence of estrogen, progesterone and human epidermal growth factor receptor2 receptors, and its mechanism may be related to different pathways. In addition, cinobufotalin is likely to exert its antitumor influences in a similar way as miconazole in MCF7 cells.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Bufanólidos/farmacología , Perfilación de la Expresión Génica , Transducción de Señal/efectos de los fármacos , Transcriptoma , Neoplasias de la Mama/patología , Caspasa 3/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , ProteolisisRESUMEN
Breast cancer (BC) has been identified as the leading malignancy in women worldwide. However, the potential molecular mechanism of microRNA (miR)203a3p in BC remains to be elucidated. The present study evaluated the expression of miR203a3p in BC and adjacent normal tissue in several publically available datasets. The distinguishability of precursor miR203a and miR203a3p in BC tissue and adjacent breast tissue was assessed using receiver operating characteristic (ROC) and summarized ROC (sROC) approaches. In addition, gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes pathway analysis and proteinprotein interaction analysis were performed to determine the potential molecular mechanism of miR203a3p in BC. It was identified that the expression of precursor miR203a was markedly upregulated in 1,077 BC tissue samples compared to 104 adjacent breast tissue samples from The Cancer Genome Atlas. Additionally, an increasing trend in miR203a3p expression was observed in 756 BC tissue samples compared with 76 adjacent breast tissue samples from the University of California Santa Cruz Xena project. In addition, a comprehensive metaanalysis suggested that the expression of miR203a3p was markedly increased in 2,444 BC tissue samples compared with 559 adjacent breast tissue samples. The area under the curve of the ROC and sROC revealed that miR203a3p expression was able to distinguish between BC tissue and adjacent breast tissue. However, miR203a3p exhibited no prognostic value in BC. The results of GO enrichment demonstrated that the miR203a target genes were associated with 'plasma membrane integrity', 'cell surface receptor linked signal and transduction' and '3',5'cyclic nucleotide phosphodiesterase activity'. 'Purine metabolism' was identified as the pathway with the most enrichment of miR203a3p target genes in BC. The present study also identified insulinlike growth factor receptor (IGF1) as a hub gene associated with miR203a in BC. In summary, miR203a3p may enhance the development and oncogenesis of BC, and IGF1 was defined as a hub gene of miR203a3p in BC.
Asunto(s)
Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Adulto , Anciano , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , Curva ROC , TranscriptomaRESUMEN
CONTEXT: Inflammatory myofibroblastic tumors are a rare type of soft-tissue tumor. Inflammatory myofibroblastic tumors are characterized by rearrangements involving the anaplastic lymphoma kinase gene locus on 2p23. CASE REPORT: We report the case of a 67-year-old Chinese male who presented with dysuria and fever. Magnetic resonance imaging showed an irregular prostatic mass with an isointense signal and obscure boundary. Histopathological evaluation showed that the mass consisted mainly of spindle-shaped cells. Immunohistochemical evaluation showed that the tumor cells were negative for anaplastic lymphoma kinase. CONCLUSIONS: Inflammatory myofibroblastic prostate tumors are rare lesions with unclear etiology. The pathological diagnosis is very important.
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Quinasa de Linfoma Anaplásico/análisis , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Neoplasias de los Tejidos Blandos/enzimología , Neoplasias de los Tejidos Blandos/patología , Anciano , Biopsia , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Resección Transuretral de la PróstataRESUMEN
The function of the expression of microRNA (miR)2245p in prostate adenocarcinoma (PCa) remains to be elucidated, therefore, the present study aimed to investigate the clinical significance and potential molecular mechanism of miR2245p in PCa. Data on the expression of miR2245p in PCa were extracted from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), ArrayExpress and previous literature, and metaanalyses with standardized mean difference (SMD) and summary receiver operating characteristic (sROC) methods were performed for statistical analyses. The prospective target genes of miR2245p were collected by overlapping the differentially expressed mRNAs in TCGA and GEO, and target genes predicted by miRWalk2.0. Subsequently, in silico analysis was performed to examine the associated pathways of miR2245p in PCa. The expression of miR2245p was markedly lower in PCa; the overall SMD was 0.562, and overall sROC area under the curve was 0.80. In addition, Kyoto Encyclopedia of Genes and Genomes analysis revealed that the prospective target genes of miR2245p were largely enriched in the amino sugar and nucleotide sugar metabolism signaling pathway, and three genes [UDPNacetylglucosamine pyrophosphorylase 1 (UAP1), hexokinase 2 (HK2) and chitinase 1 (CHIT1)] enriched in this pathway showed higher expression (P<0.05). In addition, key genes in the proteinprotein interaction network analysis [DNA topoisomerase 2α (TOP2A), ATP citrate lyase (ACLY) and ribonucleotide reductase regulatory subunit M2 (RRM2)] exhibited significantly increased expression (P<0.05). The results suggested that the downregulated expression of miR2245p may be associated with the clinical progression and prognosis of PCa. Furthermore, miR2245p likely exerts its effects by targeting genes, including UAP1, HK2, CHIT1, TOP2A, ACLY and RRM2. However, in vivo and in vitro experiments are required to confirm these findings.
Asunto(s)
Adenocarcinoma/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Neoplasias de la Próstata/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Biología Computacional , Bases de Datos Genéticas , Progresión de la Enfermedad , Regulación hacia Abajo , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Mapas de Interacción de Proteínas/genética , Transducción de Señal/genética , Tasa de SupervivenciaRESUMEN
Caspase-3 is a vital executioner molecule during the apoptotic process. Numerous studies have revealed the close association of caspase-3 expression and breast cancer. Nevertheless, the prognostic value of caspase-3 expression for patients with breast cancer remains uncertain. To thoroughly analyze the prognostic effect of caspase-3 expression on the clinicopathological features and survival of breast cancer, we conducted this meta-analysis. With various search strategies, electronic databases were comprehensively searched. A total of 3091 patients from 21 studies were ultimately obtained. The analysis results indicated that increased expression of caspase-3 had a negative influence on the overall survival (OS) of breast cancer (HR = 1.73, 95%CI 1.12-2.67, P = 0.014). Subgroup analyses based on race revealed that the value of caspase-3 for evaluating patients' OS was more useful in Asian patients (HR = 3.16, 95%CI 1.20-8.15, P = 0.020), and subgroup analyses based on study analytical methods revealed that caspase-3 was a risk factor for breast cancer patients in multivariate overall survival analyses (HR = 1.67, 95%CI 1.02-2.75, P = 0.044). As for the relationship between caspase-3 expression and breast cancer subtype as well as progression, caspase-3 might serve as a risk factor for the progestogen receptor (PR) and human epidermal growth factor receptor-2 (HER-2) subtypes (OR = 1.44, 95%CI 1.09-1.89, P = 0.010; OR = 1.76, 95%CI 1.18-2.62, P = 0.050, respectively) of breast cancer. However, no evidence showed that increased expression of caspase-3 was statistically correlated with tumor differentiation state (low/moderate or high), tumor TNM stage (I-II/III-IV) or lymph node metastasis (-/+). In conclusion, this meta-analysis revealed that increased caspase-3 expression was significantly associated with worse prognosis and two subtypes of breast cancer. More prospective studies are urgently needed to define the prognostic value of caspase-3 expression in patients with breast cancer.
RESUMEN
MicroRNAs (miRNAs or miRs) are highly conserved small noncoding RNA molecules involved in gene regulation. An increasing number of studies have demonstrated that miRNAs act as oncogenes or antioncogenes in various types of cancer, including breast cancer (BC). However, the exact role of miR6713p in BC has not yet been reported. In the present study, in vitro experiments were implemented to explore the effects of miR6713p on the proliferation and apoptosis of BC cells, and reverse transcriptionquantitative polymerase chain reaction was conducted using inhouse clinical BC samples to address the expression level and clinical value of miR6713p in BC. Simultaneously, miR6713p target genes were collected, and subsequent bioinformatics analyses were executed to probe the potential signaling pathway through which miR6713p influenced the occurrence and progression of BC. According to the results, the expression level of miR6713p was lower in BC tissues compared with that in adjacent nontumorous tissues (P=0.048), and the area under the curve was 0.697 (95% confidence interval=0.5380.856), with a sensitivity and specificity of 0.818 and 0.579, respectively. Forced miR6713p expression in the BC cell line MDAMB231 evidently arrested cell proliferation and induced cell apoptosis. Furthermore, in silico enrichment analyses suggested that miR6713p may be involved in the initiation and progression of BC through the targeting of genes associated with the Wnt signaling pathway. In conclusion, the present study findings suggested that miR6713p may function as a tumor suppressor in BC by influencing the Wnt signaling cascade, which provides a prospective molecular target for the therapy of BC.