RESUMEN
BACKGROUND: Palbociclib was the only available cyclin-dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient-reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real-world China. METHODS: An ambispective cohort study was conducted on patients with advanced HR+HER2- breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items [EORTC QLQ-C30] and EuroQoL 5 dimensions [EQ-5D]) were analyzed. The Kaplan-Meier method was used to visualize and estimate the median progression-free survival (mPFS). Log-rank tests, Cox regressions, t tests, and chi-square tests were performed for comparison. RESULTS: A total of 190 patients (median follow-up of 18.0 months) were enrolled. Palbociclib was mostly combined with aromatase inhibitors (66.3%), fulvestrant (32.6%), and tamoxifen (1.1%). The mPFS values were 21.0, 14.0, and 7.0 months with palbociclib administered in first- (n = 83), second- (n = 41) and subsequent-line settings (n = 66), respectively. Endocrine sensitivity was significantly associated with patient prognosis (mPFS: 23.0, 12.0, and 6.0 months for endocrine naïve, acquired, and primary resistant patients, respectively, p < 0.01). The outcome was worse for patients who failed to meet the inclusion criteria of PALOMA-3 than for those who met the criteria (later-line: 6.0 months vs. 9.0 months). The most common adverse events (AEs) were neutropenia (74.2%; grade 3/4: 30.0%), fatigue (48.4%), anemia (32.6%), and thrombocytopenia (22.1%). PRO data suggested that palbociclib plus ET significantly improved cognitive and emotional function, pain symptoms, and overall quality of life. CONCLUSIONS: Palbociclib is effective for front-line use and for treating endocrine-sensitive patients in real-world China and is generally well tolerated. The prevalence of AEs in the Chinese population is different from that reported in the PALOMA-2/3 trials.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Receptor ErbB-2 , Receptores de Estrógenos , Calidad de Vida , Estudios de Cohortes , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Medición de Resultados Informados por el PacienteRESUMEN
MicroRNA (miR)-1246 is abnormally expressed and has pro-oncogenic functions in multiple types of cancer. In the present study, its functions in breast cancer and the underlying mechanisms were further elucidated. The clinical relevance of miR-1246 was analyzed and its expression in clinical specimens and cell lines was examined by reverse transcription-quantitat000000ive PCR analysis. FACS was used to detect cell apoptosis and mitochondrial transmembrane potential. A Transwell system was used to detect cell migration and invasion. Luciferase assay was used to confirm the target gene of miR-1246. Xenograft and metastasis mouse models were constructed to determine the function of miR-1246 in vivo. miR-1246 was found to be negatively associated with overall survival in breast cancer. miR-1246 inhibitor could effectively increase the cytotoxicity of docetaxel (Doc) by inducing apoptosis, and impair cell migration and invasion by suppressing epithelial-to-mesenchymal transition. Nuclear factor (erythroid 2)-like factor 3 (NFE2L3) was confirmed as a new target gene of miR-1246, and its overexpression was shown to reduce drug resistance and migration of MDA-MB-231 cells. More importantly, NFE2L3-silencing attenuated the effect of miR-1246 inhibitor. Finally, the inhibition of miR-1246 effectively enhanced the cytotoxicity of Doc in xenografts and impaired breast cancer metastasis. Therefore, miR-1246 may promote drug resistance and metastasis in breast cancer by targeting NFE2L3.
RESUMEN
BACKGROUND: The incidence of papillary thyroid carcinoma (PTC) has been steadily increasing over the past decades. Hashimoto's thyroiditis (HT) is the most common autoimmune disease, and is related to the pathogenesis of PTC. Programmed death-1 (PD-1) is currently used for the treatment of PTC, but there are very few studies on the clinical value of PD-1 in the diagnosis and targeted therapy of PTC. METHODS: The expression of T, B, NK cells and PD-1 in the peripheral blood of 132 patients with PTC (PTC group), 48 patients with nodular goiter (NG group) and 63 healthy subjects (HP group) were detected by flow cytometry. The expression of plasma T3, T4, FT3, FT4, TSH, TGAb and TPO was detected by chemiluminescence immunoassay. Among 132 PTC, 49 PTC&HT and 83 PTC&noHT were included. Among 48 NG, 10 NG&HT and 38 NG&noHT were included. The expressions of programmed death- ligand1(PD-L1) in tumor tissues of PTC group and thyroid tissues of NG group, PD-1 and CD3 in tumor infiltration lymphocyte (TIL) were detected by immunohistochemistry. RESULTS: The expression of FT3, TGAb, CD3+PD-1+, CD3+CD4+PD-1+ and CD3+CD8+PD-1+ in PTC and NG was significantly higher than that in the HP group. Moreover, CD3+PD-1+, CD3+CD4+PD-1+ and CD3+CD8+PD-1+ expression had significant differences between the PTC group and the NG group. In addition, the expression of TGAb, TPO, CD3+PD-1+, CD3+CD4+PD-1+ and CD3+CD8+PD-1+ in PTC&HT group was significantly higher than that in the PTC&noHT group. While, the expression of B cells, CD3+PD-1+, CD3+CD4+PD-1+ and CD3+CD8+PD-1+ in PTC&HT group was higher than that in NG&HT group. PD-1 showed a significant correlation with PTC lymph node metastasis. CD3+PD-1+ and CD3+CD4+PD-1+ was higher in N1 stage than in N0 stage. Immunohistochemical results showed that the expression of PD-1, CD3 and PD-L1 in PTC was significantly higher than that in NG. CONCLUSIONS: T cell exhaustion might act as a biomarker for the differential diagnosis of PTC and NG. Patients with PTC&HT have obvious T cell exhaustion and increased expression of PD-1, PD-L1.Targeting the PD-1/PD-L1 pathway could be a new approach to prevent malignant transformation from HT to PTC&HT in the future.
Asunto(s)
Bocio Nodular/inmunología , Enfermedad de Hashimoto/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Subgrupos de Linfocitos T/inmunología , Cáncer Papilar Tiroideo/inmunología , Neoplasias de la Tiroides/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/sangre , Estudios de Casos y Controles , Proliferación Celular , Femenino , Bocio Nodular/sangre , Bocio Nodular/patología , Enfermedad de Hashimoto/sangre , Enfermedad de Hashimoto/patología , Humanos , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Fenotipo , Receptor de Muerte Celular Programada 1/sangre , Subgrupos de Linfocitos T/metabolismo , Cáncer Papilar Tiroideo/sangre , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/patología , Microambiente Tumoral , Adulto JovenRESUMEN
BACKGROUND: Numerous studies have shown the detrimental effects of overt hyperthyroidism on sexual functioning but a quantitative result has not yet been synthesized. AIM: To conduct a systematic review and meta-analysis that quantifies the association between overt hyperthyroidism and the risk of sexual dysfunction (SD). METHODS: A meta-analysis of studies in the literature published prior to February 1, 2020, from 4 electronic databases (MEDLINE, Embase, Cochrane Library databases, and PsychINFO) was conducted. All analyses were performed using the random-effects model comparing individuals with and without overt hyperthyroidism. OUTCOMES: The strength of the association between overt hyperthyroidism and risk of SD was quantified by calculating the relative risk (RR) and the standard mean difierences with 95% CI. The quality of evidence for the reported outcome was based on the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Of 571 publications, a total of 7 studies involving 323,257 individuals were included. Synthetic results from 7 eligible studies indicated that overt hyperthyroidism led to significant SD in both sexes (pooled RR = 2.59, 95% CI: 1.3-5.17, P = .007; heterogeneity: I2 = 98.8%, P < .001). When we analyzed the data of men and women independently, the pooled results consistently showed that men and women with overt hyperthyroidism were at over 2-fold higher risk of SD than the general populations (RR for males = 2.59, 95% CI: 1.03-6.52, P = .044; RR for females = 2.51, 95% CI: 1.47-4.28, P = .001). Combined standard mean diffierences from those studies providing the Female Sexual Function Index (FSFI) suggested that women with overt hyperthyroidism were associated with a significantly lower FSFI value in FSFI total scores, subscale sexual arousal, lubrication, orgasm, and satisfaction domain (all P < .05). The overall quality of evidence in our study was considered to be moderate. CLINICAL IMPLICATIONS: Clinicians should know the detrimental effects of overt hyperthyroidism on sexual functioning in clinical practice. Measurement of thyroid hormones should be included in the assessment of patients presenting with SD when they show symptoms of clinical hyperthyroidism. STRENGTHS & LIMITATIONS: This is the first meta-analysis quantifying the relationship between overt hyperthyroidism and the risks of SD. However, the combined results were derived from limited retrospective studies along with substantial heterogeneities. CONCLUSION: Our study has confirmed the potentially devastating sexual health consequences caused by overt hyperthyroidism. However, additional rigorous studies with sizable samples are still needed to better elucidate this evidence. Pan Y, Xie Q, Zhang Z, et al. Association Between Overt Hyperthyroidism and Risk of Sexual Dysfunction in Both Sexes: A Systematic Review and Meta-Analysis. J Sex Med 2020;17:2198-2207.
Asunto(s)
Hipertiroidismo , Disfunciones Sexuales Fisiológicas , Femenino , Humanos , Hipertiroidismo/complicaciones , Hipertiroidismo/epidemiología , Masculino , Orgasmo , Estudios Retrospectivos , Conducta Sexual , Disfunciones Sexuales Fisiológicas/epidemiología , Disfunciones Sexuales Fisiológicas/etiologíaRESUMEN
BACKGROUND: Papillary thyroid carcinoma (PTC) is an indolent tumor that is exploding with increasing thyroid nodules (TN). Environmental carcinogens, lifestyle changes increased the incidence of thyroid carcinoma. With the development of B-ultrasound imaging, more and more thyroid cancer has been found. There has been a debate about whether thyroid cancer is overtreated. METHODS: The expression of T cell subsets and plasma cytokines in 191 patients, including 79 patients with PTC (PTC group), 58 patients with thyroid nodules (TN group) and 54 healthy individuals (HP group) were analyzed by flow cytometry. RESULTS: High levels of natural killer cells (NK) were detected in PTC and TN groups than in HP group. High activities of CD8+HLA-DR+ and CD8+CD38+ showed a gradual upward trend from HP group to PTC group. The rise in the levels of TNF-α in PTC patients' was evident when compared with HP group. CD8+CD38+ showed a significant correlation with lymph node metastasis. CD8+CD38+ co-expression was higher in Nx stage than N0 stage, while the proportion of IL-10 was dramatically decreased in the Nx stage. CONCLUSIONS: These results indicated that CD8+CD38+ might act as a biomarker of PTC lymph node metastasis. The combination of CD8+HLA-DR+, CD8+CD38+ and TNF-α can be used as useful biomarkers for the early-warning indicator of PTC.
Asunto(s)
Carcinoma Papilar/inmunología , Metástasis Linfática/inmunología , Cáncer Papilar Tiroideo/inmunología , Neoplasias de la Tiroides/inmunología , Adulto , Anciano , Biomarcadores de Tumor/sangre , Carcinoma/patología , Carcinoma Papilar/patología , Femenino , Humanos , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/patologíaRESUMEN
This meta-analysis aims to determine whether autologous fat grafting (AFG) affects the risk of local-regional recurrence (LRR) in breast cancer patients. In pooled analyses of 11 eligible studies, AFG was not associated with increased LRR. Subgroup analyses showed that AFG did not increase the risk of LRR in patients undergoing breast-conserving surgery or mastectomy, in patients with in situ carcinomas or invasive carcinomas, or in patients undergoing postoperative radiotherapy.
Asunto(s)
Tejido Adiposo/trasplante , Neoplasias de la Mama/cirugía , Recurrencia Local de Neoplasia/etiología , Complicaciones Posoperatorias , Femenino , Humanos , Trasplante AutólogoRESUMEN
Background: Cancer metastasis is the leading cause of cancer-related death in breast cancer. However, our understanding of its mechanisms is still limited. At this study, the biological roles and clinical significance of NRF3 (NFE2L3, nuclear factor, Erythroid 2 Like 3) in breast cancer are evaluated for the first time. Methods: NRF3 expression in breast cancer cell lines and clinical specimens was determined by western blot and immunohistochemistry, respectively. Cell proliferation, cell cycle distribution, cell migration, and invasion were detected by MTT, colony formation, flow cytometry, and transwell assays, respectively. All other proteins were measured by western blot. The clinical significance of NRF3 was analyzed using the data from tissue microarray. Results: We found that NRF3 expression was obviously suppressed in breast cancer tissues, and negatively associated with the Lymph node metastasis status and tumor stages. Our data also indicated NRF3 expression was much higher in MCF-7 cells than that in MDA-MB-231 and SKBR3 cells which were more malignant. Silence of NRF3 in MCF-7 cells could significantly promote cell proliferation by reducing the cell number in the G0/G1 phase. Exogenous expression of NRF3 in SKBR3 and MDA-MB-231 cells effectively inhibited both cell growth and metastasis with epithelial-mesenchymal transition and MMPs expression suppressed. NRF3 overexpression also impaired the ID3 expression by inactivating the AKT signaling pathway. Exogenous expression of ID3 could not only effectively promote breast cancer cell invasion by inhibiting E-cadherin expression and upregulating MMP-2 expression, but also attenuated the inhibitory function of NRF3 on the breast cancer cell invasion. Conclusion: Our findings suggested that NRF3 inhibited breast cancer cell proliferation and metastasis via inhibiting AKT/ID3 axis at least partially, and potentially to be a valuable clinic marker in breast cancer prognosis.
RESUMEN
BACKGROUND: Cumulatively, evidences revealed that fenofibrate used in the therapy of hyperlipidemia and hypercholesterolemia has anti-cancer effect in multiple cancer types. However, its function and underlying mechanism of chemosensitization in breast cancer remain poorly understood. MATERIALS AND METHODS: The cytotoxicity of fenofibrate and anti-cancer drugs in breast cancer cells was determined by MTT. Apoptosis and mitochondrial membrane potential were measured using flow cytometry. Caspases and PARP cleavage, the Bcl-2 family members' protein expression, as well as the activation of AKT and NF-κB signaling pathways were evaluated using Western blot assay. Real-time PCR was used to determine the mRNA expression of Bcl-2 family members. RESULTS: Our data indicated that fenofibrate suppressed SKBR3 and MDA-MB-231 cell growth in a dose-dependent manner, in the same way as paclitaxel, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ABT-737, and doxorubicin. Subtoxic levels of fenofibrate significantly augmented paclitaxel, TRAIL, ABT-737, and doxorubicin-induced apoptosis in both these two cell lines. Fenofibrate-promoted chemosensitivity is predominantly mediated by caspase-9 and caspase-3 activation and mitochondrial outer membrane permeabilization. Meanwhile, chemosensitivity promoted by fenofibrate also increased the expression of Bax and Bok and decreased the expression of Mcl-1 and Bcl-xl. Mechanistically, fenofibrate effectively reduced the phosphorylation levels of AKT and NF-κB. In addition, imiquimod, an NF-κB activator, could reverse fenofibrate-induced susceptibility to ABT-737-triggered apoptosis. CONCLUSION: The present study provided the evidence of the underlying mechanisms on chemosensitization of fenofibrate by inducing the apoptosis of breast cancer in an AKT/NF-κB-dependent manner and implicated the potential application of fenofibrate in potentiating chemosensitivity in breast cancer therapy.
RESUMEN
OBJECTIVE: We aim to investigate whether the breast cancer metastasis suppressor gene, breast cancer metastasis suppressor 1 (BRMS1), is correlated with clinicopathological features of breast cancer or not. MATERIALS AND METHODS: Following a stringent inclusion and exclusion criteria, case-control studies related to the association between BRMS1 and breast cancer were selected from articles retrieved by electronic database searches. All statistical analyses were performed by Stata version 12.0 (Stata Corp, College Station, TX, USA). RESULTS: A total of 12 studies were ultimately included in this meta-analysis. Results of our meta-analysis suggested that BRMS1 protein in breast cancer tissues was significantly lower compared with normal breast tissues (odds ratio [OR] =0.08, 95% confidence interval [CI] =0.04-0.15, P < 0.001). The BRMS1 protein in metastatic breast cancer tissue was lower than that in nonmetastatic breast cancer tissue (OR = 0.20, 95% CI = 0.13-0.29, P < 0.001), and BRMS1 protein in tumor-node-metastasis (TNM) stages 1, 2 was found to be higher than TNM stages 3, 4 (OR = 4.62, 95% CI = 2.77-7.70, P < 0.001). With respect to breast cancer types, BRMS1 protein in all the three major types of breast cancer was lower than the normal tissues. We also found strong correlations between BRMS1 mRNA levels and TNM stage and tumor size. CONCLUSION: Our meta-analysis results showed that reduced BRMS1 expression level was significantly associated with clinicopathological features of breast cancer, suggesting that loss of expression or reduced levels of BRMS1 might be a strong indicator of the metastatic capacity of breast cancer, with poor prognosis.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Proteínas Represoras/genética , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Humanos , Metaanálisis como Asunto , Pronóstico , Factores de RiesgoRESUMEN
Our aim is to investigate whether or not the breast cancer metastasis suppressor 1 (BRMS1) gene expression is directly linked to clinico-pathological features of breast cancer. Following a stringent inclusion and exclusion criteria, case-control studies with associations between BRMS1 and breast cancer were selected from articles obtained by way of searches conducted through an electronic database. All statistical analyses were performed with Stata 12.0 (Stata Corp, College Station, TX, U.S.A.). Ultimately, 1,263 patients with breast cancer were found in a meta-analysis retrieved from a total that included 12 studies. Results of our meta-analysis suggested that BRMS1 protein in breast cancer tissues was significantly lower in comparison with normal breast tissues (odds ratio, OR = 0.08, 95% confidence interval (CI) = 0.04-0.15). The BRMS1 protein in metastatic breast cancer tissue was decreased than from that was found in non-metastatic breast cancer tissue (OR = 0.20, 95%CI = 0.13-0.29), and BRMS1 protein in tumor-node-metastasis (TNM) stages 1 and 2 was found to be higher than TNM stages 3 and 4 (OR = 4.62, 95%CI = 2.77-7.70). BRMS1 protein in all three major types of breast cancer was lower than that of control tissues respectively. We also found strong correlations between BRMS1 mRNA levels and TNM stage and tumor size. The results our meta-analysis showed that reduction in BRMS1 expression level was linked directly to clinico-pathological features of breast cancer significantly; therefore, suggesting the loss of expression or reduced levels of BRMS1 is potentially a strong indicator of the metastatic capacity of breast cancer with poor prognosis.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ganglios Linfáticos/patología , Proteínas Represoras/genética , Estudios de Casos y Controles , Intervalos de Confianza , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Estadificación de Neoplasias , Oportunidad Relativa , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estadística como AsuntoRESUMEN
The purpose of the present study was to investigate the serum levels of microRNA (miRNA/miR)-382-3p, -598-3p, -1246 and -184 in breast cancer patients and to assess their feasibility as biomarkers for breast cancer screening. Serum samples were obtained from 100 breast cancer patients and 40 age-matched healthy control subjects in Taizhou Central Hospital (Taizhou, Zhejiang, China) between January 2013 and September 2014. The serum expression levels of miR-382-3p, -598-3p, -1246 and -184 were determined by stem-loop reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic curves were drawn to evaluate the sensitivity and specificity of the serum miRNA expression levels for the screening of breast cancer. miR-382-3p and -1246 were significantly upregulated in the serum of the breast cancer patients, while miR-598-3p and -184 were significantly downregulated. The sensitivity and specificity to detect breast cancer were as follows: miR-382-3p, 52.0 and 92.5%; miR-598-3p, 95.0 and 85.0%; miR-1246, 93.0 and 75.0%; and miR-184, 87.5 and 71.0%, respectively. The expression levels of the four serum miRNAs were not correlated with the patients' clinical stage. In summary, miR-382-3p, -598-3p, -1246 and -184 are all involved in the development of breast cancer, and are promising biomarkers for breast cancer detection.
RESUMEN
BACKGROUND: Peptide-mediated drug delivery system (DDS) has been increasingly used to promote on-demand treatment efficacy of cancers. Herein, LTLRWVGLMS (LS10) peptide is selected as the functional ligand for specific glioma-targeting drug delivery. LS10 peptide selectively binds to NG2 proteins that are widely overexpressed in the glioma cells and restricted in normal tissue. LS10 peptide-decorated DDS is expected to hold vast promises in glioma therapy and decrease unwanted side effects. METHODS: LS10 peptide was conjugated on the surface of poly(ethylene glycol)-poly(É-caprolactone) (PEG-PCL) nanoparticles via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride/N-hydroxysulfosuccinimide coupling reaction. Using U87MG cells as the glioma cell model, cellular uptake, internalization mechanism, cellular cytotoxicity and apoptosis were investigated. 1,1'-Dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide were used as fluorescence probes to investigated in vivo glioma targeting capability of LS10-NP. The glioma therapeutic efficacy of paclitaxel-loaded LS10-NP was studied on glioma-bearing nude mice. RESULTS: The LS10-NP with size of 119 nm enhanced cellular uptake on U87MG cells, increased cytotoxicity of the loaded paclitaxel (PTX), and improved penetration in 3D U87MG glioma spheres. In vivo biodistribution experiments showed that LS10-NP exhibited the enhanced drug localization at glioma site, which resulted in prolonged survival time of glioma-bearing mice. CONCLUSION: Our results indicated that LS10 peptide-modified nanoparticulate DDS could significantly improve the anti-glioma efficacy.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Glicoles de Etileno/química , Glioma/tratamiento farmacológico , Nanopartículas/administración & dosificación , Nanopartículas/química , Péptidos/administración & dosificación , Péptidos/química , Poliésteres/química , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Glicoles de Etileno/administración & dosificación , Glicoles de Etileno/farmacocinética , Glioma/metabolismo , Masculino , Ratones , Ratones Desnudos , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Tamaño de la Partícula , Péptidos/farmacocinética , Poliésteres/administración & dosificación , Poliésteres/farmacocinética , Distribución TisularRESUMEN
BACKGROUND AND OBJECTIVES: Translesion synthesis (TLS) polymerases enable cells to bypass or overcome DNA damage during DNA replication and contributes to genomic instability and cancer. Inhibition of the expression of TLS genes enhances the sensitivity of cancer cells to cisplatin. This study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) in the TLS genes and clinical outcome of advanced non-small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. METHODS: A total of 16 SNPs were genotyped and analyzed in 302 advanced NSCLC patients (discovery set), and the results were further validated in additional 428 NSCLC patients (validation set). RESULTS: Analyses revealed significant associations of two SNPs, rs3213801 and rs3792136, with overall survival, with the lowest combined P values of 0.003 and 0.016, respectively. These effects also remained in stratification analyses by clinical variables. Furthermore, the number of risk genotypes of the two SNPs showed a cumulative effect on overall survival (P = 0.03). CONCLUSIONS: Genetic polymorphisms in the TLS genes might serve as potential predictive biomarkers of prognosis of advanced NSCLC patients treated with platinum-based chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple , Proteína FUS de Unión a ARN/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma del Pulmón , Adulto , Anciano , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Cisplatino/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , PronósticoRESUMEN
The mitotic spindle checkpoint (SAC) genes have been considered targets of anticancer therapies. Here, we sought to identify the attractive mitotic spindle checkpoint genes appropriate for human hepatocellular carcinoma (HCC) therapies. Through expression profile analysis of 137 selected mitotic spindle checkpoint genes in the publicly available microarray datasets, we showed that 13 genes were dramatically up-regulated in HCC tissues compared to normal livers and adjacent non-tumor tissues. A role of the 13 genes in proliferation was evaluated by knocking them down via small interfering RNA (siRNA) in HCC cells. As a result, several mitotic spindle checkpoint genes were required for maintaining the proliferation of HCC cells, demonstrated by cell viability assay and soft agar colony formation assay. Then we established sorafenib-resistant sublines of HCC cell lines Huh7 and HepG2. Intriguingly, increased TTK expression was significantly associated with acquired sorafenib-resistance in Huh7, HepG2 cells. More importantly, TTK was observably up-regulated in 46 (86.8%) of 53 HCC specimens. A series of in vitro and in vivo functional experiment assays showed that TTK overexpression promoted cell proliferation, anchor-dependent colony formation and resistance to sorafenib of HCC cells; TTK knockdown restrained cell growth, soft agar colony formation and resistance to sorafenib of HCC cells. Collectively, TTK plays an important role in proliferation and sorafenib resistance and could act as a potential therapeutic target for human hepatocellular carcinoma.
Asunto(s)
Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Genes cdc , Neoplasias Hepáticas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Fenilurea/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , SorafenibRESUMEN
BACKGROUND AND OBJECTIVE: Oxycodone is a semisynthetic opioid analgesic drug classed as a strong opioid. The controlled-release oxycodone tablet formulation (OCRT) was approved in China in 2004 for management of moderate to severe cancer pain. Few data about the efficacy of OCRT and clinical outcomes in Chinese patients taking this drug are available. The purpose of this study was to evaluate the efficacy and tolerability of this drug for relief of moderate to severe cancer pain in Chinese patients. METHODS: This was a prospective, open-label, multicentre clinical trial carried out in ten hospitals in Zhejiang Province, China. Patients with cancer pain with a score > or =4 (numerical rating scale) were enrolled. They received oral OCRT at an initial dosage of 5mg every 12 hours for patients scoring 4-6 and 10mg every 12 hours for patients scoring > or =7. Doses were then titrated on an individual basis. Onset of analgesic action, pain score and quality-of-life (QOL) scores - including items measuring family understanding and support, sleep, mental state, appetite, fatigue, and activities of daily life - were evaluated. Adverse effects were also documented. RESULTS: 216 patients (126 males and 90 females) aged 22-84 years were enrolled. The total mean OCRT dosage was 445.2 +/- 361.6mg (range 130-2320mg). The daily dosages of the vast majority of cases (89%) were between 10mg and 30mg. Onset of analgesic action occurred within 1 hour in 198 cases (91.7%) following administration of OCRT. 82.4% of cases were titrated to a steady dosage level within 2 days following administration of the first dose of medication. Pain score decreased significantly (p < 0.01) from 7.1 +/- 1.2 at baseline to 2.3 +/- 1.2 one week after starting medication and 1.8 +/- 0.9 four weeks after starting medication. Scores on all six QOL items increased significantly (p < 0.01) compared with baseline but showed varying rates of improvement. Adverse events included constipation, nausea, vomiting, drowsiness and dysuria. These were noted most frequently in the first week (25.5% of patients) and lessened over time. No severe adverse events were noted. CONCLUSION: We conclude that OCRT is well tolerated and effective in controlling moderate to severe cancer pain in Chinese patients.