Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 74
Filtrar
1.
Oncogene ; 39(33): 5520-5535, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32647134

RESUMO

High grade serous ovarian cancer (HGSOC) is a fatal gynecologic malignancy in the U.S. with limited treatment options. New therapeutic strategies include targeting of the cell cycle checkpoints, e.g., ATR and CHK1. We recently reported a promising clinical activity of the CHK1 inhibitor (CHK1i) prexasertib monotherapy in BRCA wild-type (BRCAwt) HGSOC patients. In this study, biopsies of treated patients and cell line models were used to investigate possible mechanisms of resistance to CHK1i. We report that BRCAwt HGSOC develops resistance to prexasertib monotherapy via a prolonged G2 delay induced by lower CDK1/CyclinB1 activity, thus preventing cells from mitotic catastrophe and cell death. On the other hand, we noted CHK1's regulation on RAD51-mediated homologous recombination (HR) repair was not altered in CHK1i-resistant cells. Therefore, CHK1i sensitizes CHK1i-resistant cells to DNA damaging agents such as gemcitabine or hydroxyurea by inhibition of HR. In summary, our results demonstrate new mechanistic insights of functionally distinct CHK1 activities and highlight a potential combination treatment approach to overcome CHK1i resistance in BRCAwt HGSOC.

2.
Radiat Oncol ; 15(1): 159, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605627

RESUMO

BACKGROUND: Proton radiotherapy has a dosimetric advantage over photon radiotherapy. Many retrospective studies have shown promising results with proton radiotherapy in treating hepatocellular carcinoma (HCC). However, clinical evidence demonstrating the benefit of protons over photons is still limited. We therefore compared the clinical outcomes of the two modalities using medical research databases from our medical foundation. METHODS: We conducted a propensity score-matched cohort study based on our multi-institution medical organization research database. From January 2007 to January 2018, a total of 413 patients (photon: 349; proton: 64) who were diagnosed with HCC and primarily treated with radiotherapy with curative intent were enrolled. Overall survival (OS) and radiation-induced liver disease (RILD) were assessed. Stratified analysis was also performed to evaluate the heterogeneous effects of the two arms. RESULTS: A total of 110 patients (photon: 55; proton: 55) were analyzed in the propensity-matched series. The matched groups were balanced for baseline tumor risk factors. Cox regression analysis revealed a significant survival benefit in the proton group (p = 0.032, HR 0.56, 95% CI 0.33-0.96). The median overall survival in the proton group was not reached and that in the photon group was 17.4 months. The biological equivalent dose of radiotherapy was significantly higher in the proton group than in the photon group (median, 96.56 Gray [relative biological effectiveness] vs. 62.5 Gray, p < 0.001). The risk of RILD was significantly lower in the proton group (11.8% vs. 36%, p = 0.004). CONCLUSIONS: Proton radiotherapy could deliver a higher radiation dose than photon radiotherapy without increasing the risk of RILD and result in a better overall survival rate for those diagnosed with HCC and treated with radiotherapy with curative intent.

3.
Biosens Bioelectron ; 164: 112320, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479341

RESUMO

In this study we developed a uniform, large-area, layered graphene composite of graphene oxide/graphene (GO/G) for the detection of circulating miRNA-21, a reliable biomarker for early cancer diagnosis. We prepared this layered composite of GO/G through low-damage plasma treatment of bilayer G. The top layer of G was oxidized (i.e., atomic layer oxidation) to form a GO layer, which acted as the bio-receptor, while retaining the properties of the bottom layer of G, which acted as an electrical response medium. With this structure, we fabricated a simple chemiresistive biosensor that could detect miRNA-21. The electrical resistance of the sensor varied linearly (R2 = 0.986) with respect to concentrations of the target miRNA-21 in the range from 10 pM to 100 nM in phosphate-buffered saline (PBS); the limit of detection was 14.6 pM. Hall measurements revealed that the mobility and concentration of the hole carriers both decreased upon increasing the target concentration, leading to the measured increase in resistivity of our chemiresistive biosensor. Furthermore, the sensor could discriminate the complementary target miRNA-21 from its single- and four-base-mismatched counterparts and another non-complementary miRNA. The ability to detect miRNA-21 in human serum albumin and bovine serum albumin was almost identical to that in PBS.

4.
Sci Rep ; 10(1): 8060, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415115

RESUMO

Our previous study demonstrated that upregulation of multiple epidermal growth factor-like domains 11 (MEGF11) gene expression is involved in the mechanism by which recurrence of Triple Negative Breast Cancer (TNBC) occurs. Our aim was to elucidate the role of MEGF11 expression in TNBC cells, both in vitro and in vivo, and in human tissue. Following MEGF11 gene knockdown (∆MEGF11) or over-expression in MDA-MB-231 and MB-468 cells, cell growth and chemokine gene expression were evaluated. In vivo, tumour growth of implanted human TNBC cells and the number of circulating 4T1 mouse tumour cells were measured. There was a significant decrease in cell growth via inhibition of AKT, NF-kB, CREB and AP-1 activation in ∆MEGF11 MDA-MB-231 and 468 cells. This also resulted, in vivo, in a suppression of tumour growth and a decrease in the number of mouse circulating 4T1 breast cancer cells. Surprisingly, overexpression of MEGF11 upregulated the expression of various chemokines and proinflammatory cytokines via AKT activation, but there was no increase in cell proliferation. MEGF11 was found to cross-talk positively with IL-17A signalling. Patients with tumours that over-expressed MEGF11 had a poorer prognosis. We conclude that MEGF11 plays an important role in tumour survival and that overexpression of MEGF11 induces both a cytokine and a chemokine cascade, which will favour the tumour microenvironment in terms of distant metastasis. MEGF11 might be a potential therapeutic target for preventing TNBC recurrence.

5.
Int J Qual Stud Health Well-being ; 15(1): 1748362, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32292126

RESUMO

Purpose: To explore the life experiences of patients with type 1 diabetes transition from adolescence into adulthood in Taiwan.Methods: Descriptive phenomenological design was used. Fourteen participants were individually interviewed using a semi-structured interview.Results: The life experiences of patients with type 1 diabetes transition from adolescence into adulthood experience a metamorphosis from awareness of responsibility to figuring out a way to care for themselves. Six themes emerged: (1) hibernation: awareness of responsibility; (2) emergence: attempts to take responsibility; (3) perseverance: encountering difficulties; (4) anxiety: multiple worries; (5) hesitation: back-and-forth," and (6) exit: finding a way out."Conclusions: During the transition phase, the participants experienced the trials of various situations. Regardless of whether they are able to independently bear the responsibilities of self-management, they all hope to turn around the challenges of disease control and take ownership of their disease. Like a butterfly that emerges from a cocoon, they hoped to overcome the dangers of taking flight through trial and error and navigating the world. The results of this study can serve as a reference for clinical care and developing localized intervention strategies targeted to the transition period between adolescence and young adulthood.

6.
Aging Cell ; 19(5): e13146, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32307902

RESUMO

Age-dependent cognitive and behavioral deterioration may arise from defects in different components of the nervous system, including those of neurons, synapses, glial cells, or a combination of them. We find that AFD, the primary thermosensory neuron of Caenorhabditis elegans, in aged animals is characterized by loss of sensory ending integrity, including reduced actin-based microvilli abundance and aggregation of thermosensory guanylyl cyclases. At the functional level, AFD neurons in aged animals are hypersensitive to high temperatures and show sustained sensory-evoked calcium dynamics, resulting in a prolonged operating range. At the behavioral level, senescent animals display cryophilic behaviors that remain plastic to acute temperature changes. Excessive cyclase activity of the AFD-specific guanylyl cyclase, GCY-8, is associated with developmental defects in AFD sensory ending and cryophilic behavior. Surprisingly, loss of the GCY-8 cyclase domain reduces these age-dependent morphological and behavioral changes, while a prolonged AFD operating range still exists in gcy-8 animals. The lack of apparent correlation between age-dependent changes in the morphology or stimuli-evoked response properties of primary sensory neurons and those in related behaviors highlights the importance of quantitative analyses of aging features when interpreting age-related changes at structural and functional levels. Our work identifies aging hallmarks in AFD receptive ending, temperature-evoked AFD responses, and experience-based thermotaxis behavior, which serve as a foundation to further elucidate the neural basis of cognitive aging.

7.
Cancer Treat Rev ; 86: 102021, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32311593

RESUMO

Ovarian cancer is the most lethal gynecological malignancy worldwide although exponential progress has been made in its treatment over the last decade. New agents and novel combination treatments are on the horizon. Among many new drugs, a series of PI3K/AKT/mTOR pathway (referred to as the PI3K pathway) inhibitors are under development or already in clinical testing. The PI3K pathway is frequently upregulated in ovarian cancer and activated PI3K signaling contributes to increased cell survival and chemoresistance. However, no significant clinical success has been achieved with the PI3K pathway inhibitor(s) to date, reflecting the complex biology and also highlighting the need for combination treatment strategies. DNA damage repair pathways have been active therapeutic targets in ovarian cancer. Emerging data suggest the PI3K pathway is also involved in DNA replication and genome stability, making DNA damage response (DDR) inhibitors as an attractive combination treatment for PI3K pathway blockades. This review describes an expanded role for the PI3K pathway in the context of DDR and cell cycle regulation. We also present the novel treatment strategies combining PI3K pathway inhibitors with DDR blockades to improve the efficacy of these inhibitors for ovarian cancer.


Assuntos
Dano ao DNA , Neoplasias Ovarianas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Animais , Replicação do DNA/efeitos dos fármacos , Feminino , Humanos , Terapia de Alvo Molecular , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Transdução de Sinais/efeitos dos fármacos
8.
EBioMedicine ; 54: 102717, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32268268

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is aggressive and has a poor prognosis. Kynurenine 3-monooxygenase (KMO), a crucial kynurenine metabolic enzyme, is involved in inflammation, immune response and tumorigenesis. We aimed to study the role of KMO in TNBC. METHODS: KMO alteration and expression data from public databases were analyzed. KMO expression levels in TNBC samples were analyzed using immunohistochemistry. Knockdown of KMO in TNBC cells was achieved by RNAi and CRISPR/Cas9. KMO functions were examined by MTT, colony-forming, transwell migration/invasion, and mammosphere assays. The molecular events were analyzed by cDNA microarrays, Western blot, quantitative real-time PCR and luciferase reporter assays. Tumor growth and metastasis were detected by orthotopic xenograft and tail vein metastasis mouse models, respectively. FINDINGS: KMO was amplified and associated with worse survival in breast cancer patients. KMO expression levels were higher in TNBC tumors compared to adjacent normal mammary tissues. In vitro ectopic KMO expression increased cell growth, colony and mammosphere formation, migration, invasion as well as mesenchymal marker expression levels in TNBC cells. In addition, KMO increased pluripotent gene expression levels and promoter activities in vitro. Mechanistically, KMO was associated with ß-catenin and prevented ß-catenin degradation, thereby enhancing the transcription of pluripotent genes. KMO knockdown suppressed tumor growth and the expression levels of ß-catenin, CD44 and Nanog. Furthermore, mutant KMO (known with suppressed enzymatic activity) could still promote TNBC cell migration/invasion. Importantly, mice bearing CRISPR KMO-knockdown TNBC tumors showed decreased lung metastasis and prolonged survival. INTERPRETATION: KMO regulates pluripotent genes via ß-catenin and plays an oncogenic role in TNBC progression.

9.
Sci Rep ; 10(1): 4861, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184406

RESUMO

This study aimed to validate the long-term prognostic value of a new clinical-genomic model, Distant Genetic Model-Clinical Variable Model 6 (DGM-CM6), developed in Asia as a prognostic panel for all subtypes of breast cancer. We included 752 operable stage I-III breast cancer patients representing all subtypes treated from 2005 to 2014 as the validation cohort. The median follow-up was 95.8 months. The low- and high-risk patients classified by DGM-CM6 (RI-DR) had significant differences in 10-year distant recurrence-free interval (DRFI) (94.1% vs. 85.0%, P < 0.0001) and relapse-free survival (RFS) (90.0% vs. 80.5%, P = 0.0003). External validation using EMTAB-365 dataset showed similar observation (P < 0.0001). DGM-CM6 was an independent prognostic factor by multivariate analysis with hazard ratios of 3.1 (1.6-6.0) for RFS (P = 0.0009) and 3.8 (1.6-9.0) for DRFI (P = 0.0028). Comparing the C-index of DGM-CM6 and PAM50-ROR scores, the former performed better than the latter in predicting long-term DRFI and RFS, especially in N0, ER/PR-positive, and HER2-negative patients.

10.
Nano Lett ; 19(12): 8972-8978, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31693379

RESUMO

Dielectric metasurfaces have recently been shown to provide an excellent platform for the harmonic generation of light due to their low optical absorption and to the strong electromagnetic field enhancement that can be designed into their constituent meta-atoms. Here, we demonstrate vacuum ultraviolet (VUV) third harmonic generation from a specially designed dielectric metasurface consisting of a titanium dioxide (TiO2) nanostructure array. The metasurface was designed to enhance the generation of VUV light at a wavelength of 185 nm by tailoring its geometric design parameters to achieve an optical resonance at the fundamental laser wavelength of 555 nm. The metasurface exhibits an enhancement factor of nominally 180 compared to an unpatterned TiO2 thin film of the same thickness, evidence of strong field enhancement at the fundamental wavelength. Mode analysis reveals that the origin of the enhancement is an anapole resonance near the pump wavelength. This work demonstrates an effective strategy for the compact generation of VUV light that could enable expanded access to this useful region of the electromagnetic spectrum.

11.
Br J Clin Pharmacol ; 85(11): 2614-2622, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31418902

RESUMO

AIMS: The aim of this study was to improve medication reconciliation and reduce the occurrence of duplicate prescriptions by pharmacists and physicians within 72 hours of hospital admission using an intelligent prescription system combined with the National Health Insurance PharmaCloud system to integrate the database with the medical institution computerized physician order entry (CPOE) system. METHODS: This 2-year intervention study was implemented in the geriatric ward of a hospital in Taiwan. We developed an integrated CPOE system linked with the PharmaCloud database and established an electronic platform for coordinated communication with all healthcare professionals. Patients provided written informed consent to access their PharmaCloud records. We compared the intervention effectiveness within 72 hours of admission for improvement in pharmacist medication reconciliation, increased at-home medications documentation and decreased costs from duplicated at-home prescriptions. RESULTS: The medication reconciliation rate within 72 hours of admission increased from 44.0% preintervention to 86.8% postintervention (relative risk = 1.97, 95% confidence interval [CI]: 1.69-2.31; P < .001). The monthly average of patients who brought and took home medications documented in the CPOE system during hospitalization increased by 7.54 (95% CI 5.58-20.49, P = .22). The monthly average of home medications documented increased by 102.52 (95% CI 38.44-166.60; P = .01). Savings on the monthly average prescription expenditures of at-home medication increased by US$ 2,795.52 (95% CI US$1310.41-4280.63; P < .01). CONCLUSION: Integrating medication data from PharmaCloud to the hospital's medical chart system improved pharmacist medication reconciliation, which decreased duplicated medications and reduced in-hospital medication costs.

12.
ACS Appl Mater Interfaces ; 11(33): 29901-29909, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31353900

RESUMO

Kirigami graphene allows a two-dimensional material to transform into a three-dimensional structure, which constitutes an effective transparent electrode candidate for photovoltaic (PV) cells having a surface texture. The surface texture of an inverted pyramid was fabricated on a Si substrate using photolithography and wet etching, followed by metal-assisted chemical etching to obtain silicon nanowires on the surface of the inverted pyramid. Kirigami graphene with a cross-pattern array was prepared using photolithography and plasma etching on a copper foil. Then, kirigami graphene was transferred onto hybrid heterojunction PV cells with a poly(ethylene terephthalate)/silicone film. These cells consisted of poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) as the p-type semiconductor, Si(100) as the inorganic n-type semiconductor, and a silver comb electrode on top of PEDOT:PSS. The conductivity of PEDOT:PSS was greatly improved. This improvement was significantly higher than that achieved by the continuous graphene sheet without a pattern. Transmission electron microscopy and Raman spectroscopy results revealed that the greater improvement with kirigami graphene was due to the larger contact area between PEDOT:PSS and graphene. By using two-layer graphene having a kirigami pattern, the power conversion efficiency, under simulated AM1.5G illumination conditions, was significantly augmented by up to 9.8% (from 10.03 to 11.01%).

13.
Int J Radiat Oncol Biol Phys ; 105(3): 637-648, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31295565

RESUMO

PURPOSE: There is no useful model for predicting the risk of recurrence in node-positive patients regardless of breast cancer subtype. We developed and validated 2 clinical-genomic models (recurrence index [RI]-local recurrence [LR]) and RI-distant recurrence (RI-DR) for stratifying these patients into low- and high-risk groups. METHODS AND MATERIALS: The 4 data sets were (1) training group (n = 112); (2) testing group (n = 46); (3) validation group (n = 388); and (4) E-MTAB-365 data set (n = 426). Patients who had undergone mastectomy or breast-conserving surgery and mRNA microarray analysis of their primary tumor tissue and had a pathologic stage of I to III were enrolled in the training, testing, and validation groups. Using preset cut-offs obtained from the training group, the models were tested and validated in the 3 other independent groups. RESULTS: In the validation data set, the RI-LR distinguished between low- and high-risk groups according to 10-year LR-free interval (100% vs 93.0%, P = .015) and relapse-free survival (RFS; 85.0% vs 76.9%, P = .032). The RI-DR distinguished the low-risk group from the high-risk group according to RFS (85.7% vs 77.4%, P = .025). RI-DR and RI-LR scores were independent prognostic factors in N1-N2 patients (hazard ratio [HR], 3.3; 95% confidence interval, 1.1-10.2; and HR, 2.7; 95% confidence interval, 1.1-6.7, respectively) by multivariate analysis. The RI-DR and RI-LR genetic models were tested similarly using the E-MTAB data set with HRs of 2.5 (P = .0048) and 2.7 (P = .0285), respectively, in node-positive patients. CONCLUSIONS: Both RI-DR and RI-LR can partition N1-N2 patients into low- and high-risk groups for RFS; however, the latter is superior for predicting locoregional recurrence.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linfonodos/patologia , Modelos Biológicos , Recidiva Local de Neoplasia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Neoplasias da Mama/classificação , Neoplasias da Mama/terapia , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Marcadores Genéticos , Humanos , Metástase Linfática , Mastectomia , Mastectomia Segmentar , Pessoa de Meia-Idade , Modelos Genéticos , Intervalo Livre de Progressão , Risco , Fatores de Tempo
14.
Artigo em Inglês | MEDLINE | ID: mdl-31238591

RESUMO

No previous studies have evaluated an oral health programme, before swallowing therapy, in patients with stroke and dysphagia in Taiwan. This randomised controlled trial evaluated the effect of an oral health programme (i.e., sputum assessment, Bass method-based tooth brushing, and tooth coating with fluoride toothpaste) before swallowing therapy. Sixty-six patients with stroke (23 female, 43 male) in our rehabilitation ward, who underwent nasogastric tube insertion, were assigned randomly to an oral care group (n = 33) and a control group (n = 33). Demographic data, oral health assessment, Functional Oral Intake Scale (FOIS) scores, Mini-Nutritional Assessment-Short Form (MNA-SF) scores, and nasogastric tube removal rates were compared between groups. We evaluated outcomes using generalised estimating equation analysis. Three weeks post-implementation, the oral care group had significant oral health improvements relative to the control group (95% CI =-2.69 to -1.25, Wald χ2 = 29.02, p < 0.001). There was no difference in the FOIS (95% CI = -0.16 to 0.89, Wald χ2 = 1.86, p > 0.05), MNA-SF (95% CI = -0.35 to 0.53, Wald χ2 =-0.17, p > 0.05), and nasogastric tube removal (p > 0.05) between groups. The oral care group had a higher, but non-significant FOIS score (3.94 vs 3.52) (p > 0.05). Routine oral health programmes implemented during stroke rehabilitation in patients with dysphagia may promote oral health and maintain oral intake.


Assuntos
Transtornos de Deglutição/terapia , Saúde Bucal , Higiene Bucal , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/terapia , Idoso , Feminino , Promoção da Saúde , Humanos , Intubação Gastrointestinal , Masculino , Estado Nutricional , Taiwan
15.
J Clin Nurs ; 28(11-12): 2253-2264, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30791155

RESUMO

AIMS AND OBJECTIVES: To determine prehospitalised diabetes-related foot ulcer (DFU) self-management behaviours and explore the factors associated with these behaviours. BACKGROUND: Although there are many studies that explore DFU prevention and treatment, to our knowledge, there are no quantitative studies of DFU self-management behaviours. DESIGN: Cross-sectional design. METHODS: From June 2015-June 2016, 199 hospitalised patients with DFU were given a survey questionnaire at a medical centre in northern Taiwan. DFU self-management behaviours, diabetes foot self-care behaviours, beliefs in regard to barriers to DFU self-management behaviours, and knowledge regarding warning signs of DFU deterioration were assessed by well-designed measurement tools. The Strengthening the Reporting of Observational Studies in Epidemiology checklist was used to ensure quality reporting during this observational study (see Supporting Information Appendix S1). RESULTS: The results revealed that 62.8% of participants never monitored their blood glucose level when they had foot ulcers, and 63.8% never sought treatment for their wounds when their wounds were not painful. After controlling for demographic and medical variables, stepwise multiple regression analysis revealed that the following eight significant variables were associated with DFU self-management behaviours: two DFU self-management barrier beliefs, foot self-care behaviour, no treatment for diabetes, poor financial status, employment, knowledge regarding the warning signs of DFU deterioration, and number of DFU hospitalisations. CONCLUSIONS: Diabetes-related foot ulcer self-management behaviours were insufficient. Some modifiable factors and high-risk groups for insufficient DFU self-management behaviour were identified. RELEVANCE TO CLINICAL PRACTICE: Diabetes-related foot ulcer self-management behaviours should be promoted. Interventions that modify the risk factors that were identified in this study can be designed to promote the performance of DFU self-management behaviours.


Assuntos
Pé Diabético/terapia , Conhecimentos, Atitudes e Prática em Saúde , Autogestão/métodos , Adulto , Estudos Transversais , Pé Diabético/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários , Taiwan
16.
EBioMedicine ; 40: 263-275, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30651219

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) remains difficult to be targeted. SET and cancerous inhibitor of protein phosphatase 2A (CIP2A) are intrinsic protein-interacting inhibitors of protein phosphatase 2A (PP2A) and frequently overexpressed in cancers, whereas reactivating PP2A activity has been postulated as an anti-cancer strategy. Here we explored this strategy in TNBC. METHODS: Data from The Cancer Genome Atlas (TCGA) database was analyzed. TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. The apoptotic cells were examined by flow cytometry and Western blot. A SET-PP2A protein-protein interaction antagonist TD19 was used to disrupt signal transduction. In vivo efficacy of TD19 was tested in MDA-MB-468-xenografted animal model. FINDINGS: TCGA data revealed upregulation of SET and CIP2A and positive correlation of these two gene expressions in TNBC tumors. Ectopic SET or CIP2A increased cell viability, migration, and invasion of TNBC cells. Notably ERK inhibition increased PP2A activity. ERK activation is known crucial for Elk-1 activity, a transcriptional factor regulating CIP2A expression, we hypothesized an oncogenic feedforward loop consisting of pERK/pElk-1/CIP2A/PP2A. This loop was validated by knockdown of PP2A and ectopic expression of Elk-1, showing reciprocal changes in loop members. In addition, ectopic expression of SET increased pAkt, pERK, pElk-1 and CIP2A expressions, suggesting a positive linkage between SET and CIP2A signaling. Moreover, TD19 disrupted this CIP2A-feedforward loop by restoring PP2A activity, demonstrating in vitro and in vivo anti-cancer activity. Mechanistically, TD19 downregulated CIP2A mRNA via inhibiting pERK-mediated Elk-1 nuclear translocation thereby decreased Elk-1 binding to the CIP2A promoter. INTERPRETATION: These findings suggested that a novel oncogenic CIP2A-feedforward loop contributes to TNBC progression and targeting SET to disrupt this oncogenic CIP2A loop showed therapeutic potential in TNBC.


Assuntos
Autoantígenos/metabolismo , Chaperonas de Histonas/metabolismo , Proteínas de Membrana/metabolismo , Proteína Fosfatase 2/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autoantígenos/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Modelos Animais de Doenças , Cloridrato de Erlotinib/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cancers (Basel) ; 11(1)2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30658422

RESUMO

Triple-negative breast cancer (TNBC) is a complex disease associated with the aggressive phenotype and poor prognosis. TNBC harbors heterogeneous molecular subtypes with no approved specific targeted therapy. It has been reported that HER receptors are overexpressed in breast cancer including TNBC. In this study, we evaluated the efficacy of varlitinib, a reversible small molecule pan-HER inhibitor in TNBC. Our results showed that varlitinib reduced cell viability and induced cell apoptosis in most TNBC cell lines but not in MDA-MB-231 cells. MEK and ERK inhibition overcame resistance to varlitinib in MDA-MB-231 cells. Varlitinib inhibited HER signaling which led to inhibition of migration, invasion and mammosphere formation of TNBC cells as well as significant suppression of tumor growth of MDA-MB-468 xenograft mouse model. In summary, these results suggest that HER signaling plays an important role in TNBC progression and that pan-HER inhibition is potentially an effective treatment for TNBC patients.

18.
Mol Oncol ; 12(10): 1706-1717, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30063110

RESUMO

Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and plays emerging roles in cancer. Activating transcription factor 6 (ATF6), one of the three major ER stress transducers, has been shown to contribute to chemoresistance by altering cancer cell survival. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogene, and its expression has been correlated with the prognosis of patients with cancer. In this study, we aimed to explore the relationship between ER stress-related ATF signaling and CIP2A. We found that CIP2A expression was positively correlated with ATF6 expression by analyzing publicly available RNA sequence data of patients with colorectal cancer (The Cancer Genome Atlas, TCGA). In addition, we demonstrated that tunicamycin-induced ER stress in vitro upregulated ATF6 and CIP2A. Mechanistically, we found that ATF6 directly bound to the CIP2A promoter and induced CIP2A gene expression, which contributed to colon cancer cell survival. Furthermore, knockdown of CIP2A reduced the viability of cells under ER stress. Most importantly, immunohistochemical analysis of a tissue microarray from a colon cancer patient cohort showed that higher expression levels of ATF6 and CIP2A were associated with a trend toward poor prognosis. Taken together, our results show that ER stress-related ATF6 upregulates CIP2A and contributes to the prognosis of colon cancer. Targeting CIP2A may disrupt ER stress-mediated colon cancer cell survival and thus improve the prognosis of patients with colon cancer.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Autoantígenos/metabolismo , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/metabolismo , Estresse do Retículo Endoplasmático , Proteínas de Membrana/metabolismo , Regulação para Cima , Idoso , Autoantígenos/genética , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Regiões Promotoras Genéticas/genética , Modelos de Riscos Proporcionais , Ligação Proteica , Estabilidade Proteica , Análise de Sobrevida , Transcrição Genética
19.
Oncol Lett ; 16(2): 2319-2325, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30008935

RESUMO

Previous studies have indicated that certain microRNAs (miRNAs/miRs) function as either tumor suppressors or oncogenes in human cancer. The present study identified the miR-23a/27a/24-2 cluster, containing miR-23, miR-27a and miR-24, as an oncogene in gastric cancer. The expression of the miR-23a/27a/24-2 cluster was upregulated in clinical gastric cancer tissues. Transfection with inhibitors of miR-23a, miR-27a, or miR-24, either independently or together, repressed in vitro colony formation and in vivo tumor formation. The miR23a/27a/24-2 cluster inhibitors repressed the growth of gastric cancer cells in a synergistic manner. In addition, treatment with lower doses of the miRNA inhibitor mixture induced the formation of apoptotic bodies. According to computational predictions using TargetScan, suppressor of cytokine-induced signaling 6 (SOCS6) was identified as one of the downstream target genes of the miR-23a/27a/24-2 cluster. The expression of SOCS6 was significantly lower in tumor tissues than in matched normal tissues (P<0.01) and was associated with poor survival (P<0.00001). Taken together, these results strongly suggested that the miR-23a/27a/24-2 cluster may mediate the progression of gastric cancer through the suppression of SOCS6 expression. The present study also provides a novel molecular target for the development of an anti-gastric cancer agent.

20.
Oncotarget ; 9(33): 23173-23182, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29796180

RESUMO

There had been several studies using gene-expression profiling in predicting distant recurrence in breast cancer. In this study, we developed an 18-gene classifier (18-GC) to predict distant recurrence of breast cancer and compared it with the 21-gene panel (Oncotype DX®, ODx) in performance. Included were 224 breast cancer patients with positive hormonal receptor (HR+) and negative human epidermal growth factor receptor 2 (HER2-). We compared the demographic, clinical, and survival information of the patients, and further compared the prediction of recurrence risk obtained by using the 18-GC with that by ODx. To have the best combined sensitivity and specificity, receiver operating characteristics (ROC) curve analysis was performed to determine the cutoff values for several breakpoint scores. For the new 18-GC, a breakpoint score of 21 was adopted to produce a combined highest sensitivity (95%) and specificity (39%) in detecting distant recurrence. At this breakpoint score, 164 of the 224 patients were classified by the 18-GC in the same risk level as by ODx, giving a concordance rate of 73%. Along with patient age and tumor stage, this 18-GC was found to be an independent significant prognostic factor of distant metastasis of breast cancer. We have thus created a new gene panel assay for prediction of distant recurrence in HR+ and HER2- breast cancer patients. With a high concordance rate with ODx, this new assay may serve as a good tool for individual breast cancer patients to make an informed decision on whether adjuvant chemotherapy should be performed post-surgery.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA