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Differentiating cancer subtypes is crucial to guide personalized treatment and improve the prognosis for patients. Integrating multi-omics data can offer a comprehensive landscape of cancer biological process and provide promising ways for cancer diagnosis and treatment. Taking the heterogeneity of different omics data types into account, we propose a hierarchical multi-kernel learning (hMKL) approach, a novel cancer molecular subtyping method to identify cancer subtypes by adopting a two-stage kernel learning strategy. In stage 1, we obtain a composite kernel borrowing the cancer integration via multi-kernel learning (CIMLR) idea by optimizing the kernel parameters for individual omics data type. In stage 2, we obtain a final fused kernel through a weighted linear combination of individual kernels learned from stage 1 using an unsupervised multiple kernel learning method. Based on the final fusion kernel, k-means clustering is applied to identify cancer subtypes. Simulation studies show that hMKL outperforms the one-stage CIMLR method when there is data heterogeneity. hMKL can estimate the number of clusters correctly, which is the key challenge in subtyping. Application to two real data sets shows that hMKL identified meaningful subtypes and key cancer-associated biomarkers. The proposed method provides a novel toolkit for heterogeneous multi-omics data integration and cancer subtypes identification.
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Aprendizaje Profundo , Neoplasias , Humanos , Multiómica , Neoplasias/genética , Análisis por Conglomerados , Simulación por Computador , Biomarcadores de Tumor/genéticaRESUMEN
OBJECTIVE: This study intends to conquer the mystery of microRNA-16-5p/erythropoietin-producing hepatocellular A1/nuclear factor-κB signaling (miR-16-5p/EPHA1/NF-κB signaling) in breast cancer. METHODS: Expression of miR-16-5p, EPHA1 and NF-κB signaling-related proteins were detected. Gene overexpression or silencing was used to examine the biological roles of bone marrow mesenchymal stem cells (BMSCs)-derived exo-miR-16-5p in breast cancer. The effect of exo-miR-16-5p on tumorigenesis of breast cancer was confirmed by the xenograft nude mouse model. RESULTS: Low miR-16-5p and high EPHA1 expression were examined in breast cancer. BMSCs-derived exosomes, up-regulated miR-16-5p or down-regulated EPHA1 restrained epithelial-mesenchymal transition (EMT) of breast cancer cells and tumor growth in nude mice. Down-regulated miR-16-5p or up-regulated EPHA1 activated NF-κB signaling. Knockdown of EPHA1 or inhibition of NF-κB signaling reversed the effects of down-regulated miR-16-5p on breast cancer cells. CONCLUSION: BMSCs-derived exosomal miR-16-5p hinders breast cancer cells progression via EPHA1/NF-κB signaling axis.
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Células Madre Mesenquimatosas , MicroARNs , Neoplasias , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal , Células Madre Mesenquimatosas/metabolismo , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/metabolismo , FN-kappa B/metabolismo , Receptor EphA1/metabolismoRESUMEN
Drug resistance currently represents a daunting challenge in the treatment of breast cancer patients. With an increased understanding of the underlying mechanisms of drug resistance, the role of extracellular vesicles (EVs) in the development of chemo-insensitivity attracts extensive attention. EVs are membrane-limited, cell type-dependent vesicles that are secreted by normal or malignant cells. EVs comprise various types of contents, including genetic cargoes, proteins, and specific lipids. The characteristics of the contents determine their specific functions in not only physiological but also pathological conditions. It has been demonstrated that miRNAs and proteins in EVs are strongly correlated with breast cancer drug resistance. Additionally, they may exert an influence on de novo and acquired resistance bioprocesses. With the advances in extraction and detection technologies, EVs have also been employed to precisely diagnose and predict the outcome of therapy in breast cancer. On the other hand, they can also be exploited as efficient delivery system in future anticancer applications. In this paper, we summarized relative mechanisms concerning the relationship between EVs and breast cancer drug resistance, and then, we provide up-to-date research advances in the clinical application of EVs.
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Neoplasias de la Mama/tratamiento farmacológico , Vesículas Extracelulares/fisiología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/fisiología , Neoplasias de la Mama/diagnóstico , Resistencia a Antineoplásicos , Exosomas/fisiología , Femenino , Humanos , MicroARNs/fisiología , Proteínas de Neoplasias/fisiologíaRESUMEN
Metallic nanoparticles (NPs) have potential applications in industry and medicine, but they also have the potential to cause many chronic pulmonary diseases. Mechanisms for their cytotoxicity, glucose and energy metabolism responses need to be fully explained in lung epithelial cells after treatment with metallic nanoparticles. In our study, two different metallic nanoparticles (Fe2 O3 and ZnO) and two cell-based assays (BEAS-2B and A549 cell lines) were used. Our findings demonstrate that ZnO nanoparticles, but not Fe2 O3 nanoparticles, induce cell cycle arrest, cell apoptosis, reactive oxygen species (ROS) production, mitochondrial dysfunction and glucose metabolism perturbation, which are responsible for cytotoxicity. These results also suggest that the glucose metabolism and bioenergetics had a great potential in evaluating the cytotoxicity and thus were very helpful in understanding their underlying molecular mechanisms.
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Compuestos Férricos/toxicidad , Glucosa/metabolismo , Nanopartículas del Metal/toxicidad , Mucosa Respiratoria/efectos de los fármacos , Óxido de Zinc/toxicidad , Apoptosis/efectos de los fármacos , Western Blotting , Ciclo Celular/efectos de los fármacos , Línea Celular , Glucosa/análisis , Humanos , Pulmón/citología , Pulmón/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Especies Reactivas de Oxígeno/análisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Mucosa Respiratoria/química , Mucosa Respiratoria/citologíaRESUMEN
Recent studies have demonstrated that specific miRNAs, such as miR-221/222, may be responsible for tamoxifen resistance in breast cancer. Secreted miRNAs enclosed in exosomes can act as intercellular bio-messengers. Our objective is to investigate the role of secreted miR-221/222 in tamoxifen resistance of ER-positive breast cancer cells. Transmission electron microscopy analysis and nanoparticle tracking analysis were performed to determine the exosomes difference between MCF-7(TamR) (tamoxifen resistant) and MCF-7(wt) (tamoxifen sensitive) cells. PKH67 fluorescent labeling assay was used to detect exosomes derived from MCF-7(TamR) cells entering into MCF-7(wt) cells. The potential function of exosomes on tamoxifen resistance transmission was analyzed with cell viability, apoptosis ,and colony formation. MiRNA microarrays and qPCR were used to detect and compare the miRNAs expression levels in the two cells and exosomes. As the targets of miR-221/222, p27 and ERα were analyzed with western blot and qPCR. Compared with the MCF-7(wt) exosomes, there were significant differences in the concentration and size distribution of MCF-7(TamR) exosomes. MCF-7(wt) cells had an increased amount of exosomal RNA and proteins compared with MCF-7(TamR) cells. MCF-7(TamR) exosomes could enter into MCF-7(wt) cells, and then released miR-221/222. And the elevated miR-221/222 effectively reduced the target genes expression of P27 and ERα, which enhanced tamoxifen resistance in recipient cells. Our results are the first to show that secreted miR-221/222 serves as signaling molecules to mediate communication of tamoxifen resistance.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/biosíntesis , Exosomas/genética , MicroARNs/genética , Tamoxifeno/farmacología , Apoptosis/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/genética , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/genética , Exosomas/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Antígeno Nuclear de Célula en Proliferación/biosíntesis , Antígeno Nuclear de Célula en Proliferación/genéticaRESUMEN
BACKGROUND: Tamoxifen, an endocrine therapy drug used to treat breast cancer, is designed to interrupt estrogen signaling by blocking the estrogen receptor (ER). However, many ER-positive patients are low reactive or resistant to tamoxifen. Metformin is a widely used anti-diabetic drug with noteworthy anti-cancer effects. We investigated whether metformin has the additive effects with tamoxifen in ER-positive breast cancer therapy. METHODS: The efficacy of metformin alone and in combination with tamoxifen against ER-positive breast cancer was analyzed by cell survival, DNA replication activity, plate colony formation, soft-agar, flow cytometry, immunohistochemistry, and nude mice model assays. The involved signaling pathways were detected by western blot assay. RESULTS: When metformin was combined with tamoxifen, the concentration of tamoxifen required for growth inhibition was substantially reduced. Moreover, metformin enhanced tamoxifen-mediated inhibition of proliferation, DNA replication activity, colony formation, soft-agar colony formation, and induction of apoptosis in ER-positive breast cancer cells. In addition, these tamoxifen-induced effects that were enhanced by metformin may be involved in the bax/bcl-2 apoptotic pathway and the AMPK/mTOR/p70S6 growth pathway. Finally, two-drug combination therapy significantly inhibited tumor growth in vivo. CONCLUSION: The present work shows that metformin and tamoxifen additively inhibited the growth and augmented the apoptosis of ER-positive breast cancer cells. It provides leads for future research on this drug combination for the treatment of ER-positive breast cancer.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Metformina/farmacología , Receptores de Estrógenos/metabolismo , Tamoxifeno/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales , Ratones , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
HER2-overexpressing breast cancers often show hyperactivation of the HER2/AKT/mTOR signaling pathway. Lapatinib is an oral dual tyrosine kinase inhibitor (TKI) that targets both EGFR and HER2 to inhibit the proliferation of breast cancer cells. However, it is obscure whether and how lapatinib could induce autophagy in breast cancer cells, an important cell response with drug treatment. In this study, we investigated the apoptosis and the autophagy in the HER2-overexpressing breast cancer cells BT474 and AU565 treated with lapatinib, and further examined their relationship. Lapatinib inhibited the proliferation and the rate of DNA synthesis in HER2-positive cells, as observed by MTT, colony formation and EDU assays. Lapatinib not only induced apoptosis accompanied by an increased expression of cleaved Caspase-3 and cleaved PARP, but it also induced autophagy in vitro, as confirmed by electron microscopy (EM), acridine orange (AO) staining and LC3-II expression. Meanwhile, lapatinib inhibited the phosphorylation of HER2, AKT, mTOR, and p70S6K, whereas that of AMPK was activated. When the cells were pre-incubated with 3-Methyladenine (3-MA), the specific autophagy inhibitor, the growth inhibitory ratio and apoptosis rate were frustrated, whereas colony formation and DNA synthesis ability were encouraged. In addition, 3-MA application could up-regulate Caspase-3 and PARP expression, compared with the treatment with lapatinib alone. The addition of 3-MA could attenuate the inhibitory role on HER2/AKT/mTOR pathway and the active role on AMPK that was raised by lapatinib. Therefore, lapatinib simultaneously induced both apoptosis and autophagy in the BT474 and AU565 cells, and in these settings, autophagy facilitates apoptosis.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Quinazolinas/administración & dosificación , Receptor ErbB-2/genética , Adenina/administración & dosificación , Adenina/análogos & derivados , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lapatinib , Fosforilación , Inhibidores de Proteínas Quinasas , Receptor ErbB-2/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
Periodontal disease is the most common oral disease seen in dogs, and its routine treatment usually involves dental scaling. Platelet-rich plasma (PRP) therapy may enhance the effectiveness of treatment of periodontal disease, delay the progression of the disease and decrease the time under anesthesia. However, its application in dogs is rarely discussed. The objective of this study was to evaluate the benefits of activated PRP for treatment of periodontal disease in dogs. 43 mL of whole blood was collected from six adult dogs and PRP extracted using the double centrifugation tube method. Subsequently, the PRP was activated using calcium chloride (A-PRP). Significantly elevated concentrations of PDGF-BB (7000.28 pg/mL), TGF-ß (378.98 pg/mL), and VEGF (7.14 pg/mL) were detected in the A-PRP. Additionally, three of the dogs with stage 2-3 periodontal disease were enrolled in the clinical trial. Periodontal pocket depth, stage of periodontal disease, gingival index, horizontal bone loss, and alveolar bone density involving the maxillary third and fourth premolar and first molar teeth (107, 108, 109, 207, 208, and 209) were evaluated. Teeth were treated by dental scaling alone (control group) or by dental scaling followed by submucosal injection of 0.1 mL A-PRP per site. After 56 days, significant improvement in periodontal pocket depth, stage of periodontal disease, gingival index, and horizontal bone loss was observed in dogs injected with A-PRP. The high concentrations of growth factors in A-PRP likely contributed to this effect. The use of submucosal injections of A-PRP to treat canine stage 2-3 periodontal disease appears safe and effective for clinical practice.
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Enfermedades de los Perros , Plasma Rico en Plaquetas , Perros , Animales , Bolsa Periodontal/veterinaria , Diente Molar , Enfermedades de los Perros/terapiaRESUMEN
Introduction: Alzheimer's disease (AD) is a complex neurodegenerative disease with high heritability. Compared to autosomes, a higher proportion of disorder-associated genes on X chromosome are expressed in the brain. However, only a few studies focused on the identification of the susceptibility loci for AD on X chromosome. Methods: Using the data from the Alzheimer's Disease Neuroimaging Initiative Study, we conducted an X chromosome-wide association study between 16 AD quantitative biomarkers and 19,692 single nucleotide polymorphisms (SNPs) based on both the cross-sectional and longitudinal studies. Results: We identified 15 SNPs statistically significantly associated with different quantitative biomarkers of the AD. For the cross-sectional study, six SNPs (rs5927116, rs4596772, rs5929538, rs2213488, rs5920524, and rs5945306) are located in or near to six genes DMD, TBX22, LOC101928437, TENM1, SPANXN1, and ZFP92, which have been reported to be associated with schizophrenia or neuropsychiatric diseases in literature. For the longitudinal study, four SNPs (rs4829868, rs5931111, rs6540385, and rs763320) are included in or near to two genes RAC1P4 and AFF2, which have been demonstrated to be associated with brain development or intellectual disability in literature, while the functional annotations of other five novel SNPs (rs12157031, rs428303, rs5953487, rs10284107, and rs5955016) have not been found. Discussion: 15 SNPs were found statistically significantly associated with the quantitative biomarkers of the AD. Follow-up study in molecular genetics is needed to verify whether they are indeed related to AD. The findings in this article expand our understanding of the role of the X chromosome in exploring disease susceptibility, introduce new insights into the molecular genetics behind the AD, and may provide a mechanistic clue to further AD-related studies.
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Necroptosis is a genetically regulated form of necrotic cell death that has emerged as an important pathway in cancers. Long non-coding RNAs (lncRNAs) are key regulators of breast cancer development. Nevertheless, few studies are reporting the effect of lncRNAs in necroptosis processes and the role of necroptosis-related lncRNAs (NRLs). The present study aimed to construct a prognostic model based on NRLs in breast cancer. NRLs were identified by combining expression profiling data from The Cancer Genome Atlas (TCGA) with necroptosis-related genes. The non-negative matrix factorization (NMF) clustering analysis was conducted to identify molecular subtypes of BC, and the clinical outcome and tumor-infiltrating immune cells (TIICs) in the different molecular subtypes were analyzed. Four molecular subtypes based on NRLs were identified, and these four molecular subtypes could predict clinical features, prognosis, and tumor-infiltrating immune cells (TIICs). A 4-NRLs signature and nomogram were established and validated its predictive capability of overall survival (OS) in breast cancer patients. Analyses of clinicopathological features, prognosis, TIICs, tumor microenvironment (TME), somatic mutations, and drug response revealed significant differences between the two risk groups. In addition, we found that low-risk patients exhibited higher levels of immune checkpoints and showed higher immunogenicity in immunophenoscore (IPS) analysis. In conclusion, we constructed a prognostic model based on the expression profile of NRLs, which may facilitate the assessment of patient prognosis, immunotherapeutic responses, and maybe a promising therapeutic target in clinical practice.
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Neoplasias de la Mama , ARN Largo no Codificante , Neoplasias de la Mama/genética , Femenino , Humanos , Necroptosis/genética , Nomogramas , Pronóstico , ARN Largo no Codificante/genética , Microambiente Tumoral/genéticaRESUMEN
Lower-grade gliomas (LGG), characterized by heterogeneity and invasiveness, originate from the central nervous system. Although studies focusing on molecular subtyping and molecular characteristics have provided novel insights into improving the diagnosis and therapy of LGG, there is an urgent need to identify new molecular subtypes and biomarkers that are promising to improve patient survival outcomes. Here, we proposed a joint similarity network fusion (Joint-SNF) method to integrate different omics data types to construct a fused network using the Joint and Individual Variation Explained (JIVE) technique under the SNF framework. Focusing on the joint network structure, a spectral clustering method was employed to obtain subtypes of patients. Simulation studies show that the proposed Joint-SNF method outperforms the original SNF approach under various simulation scenarios. We further applied the method to a Chinese LGG data set including mRNA expression, DNA methylation and microRNA (miRNA). Three molecular subtypes were identified and showed statistically significant differences in patient survival outcomes. The five-year mortality rates of the three subtypes are 80.8%, 32.1%, and 34.4%, respectively. After adjusting for clinically relevant covariates, the death risk of patients in Cluster 1 was 5.06 times higher than patients in other clusters. The fused network attained by the proposed Joint-SNF method enhances strong similarities, thus greatly improves subtyping performance compared to the original SNF method. The findings in the real application may provide important clues for improving patient survival outcomes and for precision treatment for Chinese LGG patients. An R package to implement the method can be accessed in Github at https://github.com/Sameerer/Joint-SNF.
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ETHNOPHARMACOLOGICAL RELEVANCE: Crassostrea gigas Thunberg and other oysters have been traditionally used in China as folk remedies to invigorate the kidney and as natural aphrodisiacs to combat male impotence. AIM OF THE STUDY: Erectile dysfunction (ED) has become a major health problem for the global ageing population. The aim of this study is therefore to evaluate the effect of peptide-rich preparations from C. gigas oysters on ED and related conditions as increasing evidence suggests that peptides are important bioactive components of marine remedies and seafood. MATERIALS AND METHODS: Crassostrea oyster peptide (COP) preparations COP1, COP2 and COP3 were obtained from C. gigas oysters by trypsin, papain or sequential trypsin-papain digestion, respectively. The contents of testosterone, cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) and the activity of nitric oxide synthase (NOS) in mice and/or cells were measured by enzyme-linked immunosorbent assays. Real-time PCR was used to assess the expression of genes associated with sex hormone secretion pathways. The model animal Caenorhabditis elegans was also used to analyze the gene expression of a conserved steroidogenic enzyme. In silico analysis of constituent peptides was performed using bioinformatic tools based on public databases. RESULTS: The peptide-rich preparation COP3, in which >95% peptides were <3000 Da, was found to increase the contents of male mouse serum testosterone and cAMP, both of which are known to play important roles in erectile function, and to increase the activity of mouse penile NOS, which is closely associated with ED. Further investigation using mouse Leydig-derived TM3 cells demonstrates that COP3 was able to stimulate the production of testosterone as well as NO, a pivotal mediator of penile erection. Real-time PCR analysis reveals that COP3 up-regulated the expression of Areg and Acvr2b, the genes known to promote sex hormone secretion, but not Fst, a gene involved in suppressing follicle-stimulating hormone release. Furthermore, COP3 was also shown to up-regulate the expression of let-767, a well-conserved C. elegans gene encoding a protein homologous to human 17-ß-hydroxysteroid dehydrogenases. Preliminary bioinformatic analysis using the peptide sequences in COP3 cryptome identified 19 prospective motifs, each of which occurred in more than 10 peptides. CONCLUSIONS: In this paper, Crassostrea oyster peptides were prepared by enzymatic hydrolysis and were found for the first time to increase ED-associated biochemical as well as molecular biology parameters. These results may help to explain the ethnopharmacological use of oysters and provide an important insight into the potentials of oyster peptides in overcoming ED-related health issues.
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Factores Biológicos/aislamiento & purificación , Factores Biológicos/farmacología , Crassostrea/enzimología , Fragmentos de Péptidos/aislamiento & purificación , Fragmentos de Péptidos/farmacología , Testosterona/sangre , Animales , Caenorhabditis elegans , Células Cultivadas , Biología Computacional/métodos , Relación Dosis-Respuesta a Droga , Pruebas de Enzimas/métodos , Hidrólisis , Masculino , RatonesRESUMEN
Androgen is known to regulate microRNA-135a (miR-135a) and can be regulated by androgen, suggesting that it may contribute to polycystic ovary syndrome (PCOS) with hyperandrogenism. However, its roles and mechanisms of action in PCOS are unknown. In this study, the role and molecular mechanisms underlying miR-135a in granulosa cells (GCs) in PCOS were evaluated. miR-135a expression was upregulated in patients with PCOS and in GCs isolated from patients compared with that in the respective controls (P < 0.01), as determined by RT-qPCR. The overexpression of miR-135a inhibited GC proliferation and induced GC apoptosis, as observed by CCK-8 assay and apoptosis assay. Furthermore, miR-135a overexpression increased the expression of double-strand break maker, γH2AX, as confirmed by western blotting. Our results further suggest that these effects were mediated via downregulation of vascular endothelial growth factor C (VEGFC), which was identified as a direct target of miR-135a. Moreover, levels of VEGFC and miR-135a expression showed a negative correlation. These findings indicate that miR-135a promotes apoptosis and the DNA damage response in GCs in PCOS, likely via VEGFC signaling. This study provides novel insights into GC dysregulation in PCOS and suggests that miR-135a is a promising therapeutic target for PCOS treatment.
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Apoptosis/fisiología , Células de la Granulosa/metabolismo , Células Lúteas/metabolismo , MicroARNs/biosíntesis , Síndrome del Ovario Poliquístico/metabolismo , Factor C de Crecimiento Endotelial Vascular/biosíntesis , Adulto , Células Cultivadas , Femenino , Expresión Génica , Células de la Granulosa/patología , Humanos , Células Lúteas/patología , MicroARNs/genética , Síndrome del Ovario Poliquístico/patología , Factor C de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor C de Crecimiento Endotelial Vascular/genética , Adulto JovenRESUMEN
BACKGROUND: Discussions about racism, ethnicity, sexism, discrimination, and diversity have increased within medicine, and their impact on the physician workforce, advancement, hiring, wage inequities, mistreatment, and scholarly output, to name a few. Most medical organizations have created policies and initiatives on diversity and inclusion, focusing on supporting underrepresented minorities. Similar discussions are taking place online, including on Twitter, via specific hashtags, such as #BlackMenInMedicine, #ILookLikeASurgeon. News reports suggested some of these hashtags were "trending." We set out to assess selected hashtags and analyze their spread, as well as whether or how health professional organizations publicized or amplified this emerging discourse on Twitter. METHODOLOGY: We computed tweet volume, retweet volume impressions, and spread for selected hashtags and for health-profession organizations. RESULTS: The overall volume was average or below average when compared with all active Twitter users; however, the retweet percentage was 60%, suggesting high levels of engagement. There was modest spread of most of the messages containing the hashtags, with the exception of #ilooklikeasurgeon tweets, due to its relationship to the cover of a major nonmedical magazine. Spread for some hashtags, despite very low initial retweets, was increased due to retweeting by accounts with high volume of followers. Medical societies' contributions to dissemination were very minor. CONCLUSION: Strengthening, deepening and, ultimately, expanding the conversation on diversity and inclusion in medicine on Twitter requires an intentional and strategic use of hashtags, photographs and links; Engaging "influencers" such as mainstream media and medical organizations is also critical to more widespread dissemination.
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Negro o Afroamericano/estadística & datos numéricos , Diversidad Cultural , Empleos en Salud/estadística & datos numéricos , Medios de Comunicación Sociales/estadística & datos numéricos , Sociedades Médicas/estadística & datos numéricos , Comunicación , Femenino , Humanos , Masculino , Racismo/prevención & control , Racismo/estadística & datos numéricos , Sexismo/prevención & control , Sexismo/estadística & datos numéricosRESUMEN
Chemo-resistance presents a difficult challenge for the treatment of breast cancer. Our previous study showed that N-Myc downstream-regulated gene 2 (NDRG2) is involved in p53-mediated apoptosis induced by chemotherapy, through a mechanism that has so far remained obscure. Here, we explored the role of NDRG2 in chemo-resistance with a focus on Adriamycin (ADR) and found that NDRG2 expression decreased in ADR resistance breast cancer cells. Interestingly, NDRG2 can promote ADR sensitivity by inhibiting proliferation, enhancing cellular damage responses, and promoting apoptosis in a p53-dependent manner. We also found that NDRG2 could upregulate Bad expression by increasing its half-life, which is associated with p53 to mitochondria. Hence, our collective data provided the ï¬rst evidence that NDRG2 promoting sensitivity of breast cancer is dependent on p53 by preventing p53 from entering the nucleus rather than changing its expression.
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Antibióticos Antineoplásicos/farmacología , Neoplasias de la Mama/patología , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteína Letal Asociada a bcl/metabolismo , Antibióticos Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Semivida , Humanos , Inmunoprecipitación , Mitocondrias/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Regulación hacia Arriba , Proteína Letal Asociada a bcl/genéticaRESUMEN
Docetaxel is commonly used as an effective chemotherapeutic agent in breast cancer treatment, but the underlying mechanisms of drug resistance are not fully understood. The purpose of this study was to investigate the possible role of miR-129-3p in breast cancer cell resistance to docetaxel. MiR-129 and miR-129-3p inhibitor were transfected into breast cancer cells to investigate their effects on chemoresistance to docetaxel. The function of miR-129-3p was evaluated by apoptosis, cell proliferation, and cell cycle assays. We found that miR-129-3p was up-regulated in MDA-MB-231/Doc cells, concurrent with CP110 down-regulation, compared to the parental MDA-MB-231 cells. In vitro drug sensitivity assays demonstrated that miR-129-3p inhibition sensitized MDA-MB-231/Doc and MCF-7 cells to docetaxel, whereas miR-129 overexpression enhanced MDA-MB-231 and MCF-7 cell resistance to docetaxel. Ectopic miR-129 expression reduced CP110 expression and the luciferase activity of a CP110 3' untranslated region-based reporter construct in MDA-MB-231 cells, suggesting that CP110 is a direct miR-129-3p target. We demonstrated that restoration of CP110 expression in MDA-MB-231 and MCF-7 cells by miR-129 overexpression rendered the cells sensitive to docetaxel. In a nude xenograft model, miR-129 up-regulation significantly decreased MDA-MB-231 cells' response to docetaxel. Our findings suggest that miR-129-3p down-regulation potentially sensitizes breast cancer cells to docetaxel treatment.