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AIMS: This investigation aims to elucidate the treatment status of advanced HR+/HER2- breast cancer patients in Hunan Province of Central Southern China from November 2021 to December 2022. METHODS: Data from 301 patients with advanced HR+/HER2- breast cancer were collected from the breast cancer investigation project in Hunan under the guidance of the Chinese Society of Clinical Oncolfogy (CSCO). The data included the clinical characteristics of patients and the status of first-line and second-line rescue treatment. RESULTS: First-line chemotherapy and endocrine therapy for mBC accounted for 40% (121/301) and 60% (180/301) of treatments, respectively. AI (21%), AI plus CDK4/6 inhibitor (28%), and fulvestrant (24%) or fulvestrant plus CDK4/6 inhibitor (18%) were the most common first-line endocrine therapies. Taxane-based chemotherapy was the most common first-line chemotherapy (59%). Second-line chemotherapy and endocrine therapy for mBC accounted for 43% (72/166) and 57% (94/166) of treatments, respectively. Fulvestrant (23%) or fulvestrant plus CDK4/6 inhibitor (29%) were the most common second-line endocrine therapies. The prevalences of AI and AI plus CDK4/6 inhibitor decreased to 19% and 11%, respectively. T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Third-line chemotherapy was more prevalent than endocrine therapy (57% vs. 41%). T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Fulvestrant plus CDK4/6 inhibitor was the most common endocrine therapy (33%). AI, AI plus CDK4/6 inhibitor, and fulvestrant accounted for 21%, 12% and 18% of third-line endocrine therapies, respectively. CONCLUSIONS: Compared to chemotherapy, endocrine therapy was a more favorable choice for first-line and second-line treatment for HR+/HER2- advanced breast cancer patients in Hunan Province.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Receptor ErbB-2 , Receptores de Estrógenos , Receptores de Progesterona , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , China/epidemiología , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Persona de Mediana Edad , Estudios Transversales , Adulto , Receptores de Estrógenos/metabolismo , Anciano , Receptores de Progesterona/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Inetetamab is a novel recombinant humanized anti-HER2 monoclonal antibody. This study aimed to evaluate the efficacy and safety of inetetamab and predictive factors for response in HER2-positive metastatic breast cancer (MBC) patients. METHODS: A cohort of HER2-positive MBC patients who received inetetamab-based therapy between June 2020 and August 2021 was evaluated. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Adverse events (AEs) were graded according to the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 141 patients were included in the final analysis. The median PFS of the entire cohort was 7.1 months. The median number of treatment lines administered was three. The ORR was 36.9 %, and the DCR was 80.9 %. The most frequently employed treatment strategy was inetetamab + chemotherapy (49/141, 34.8 %), followed by inetetamab + HER2-tyrosine kinase inhibitors (HER2-TKIs) + chemotherapy, inetetamab + pertuzumab + chemotherapy, inetetamab + endocrine treatment and inetetamab + HER2-TKIs. Cox multivariate analysis revealed that PFS was associated with liver metastasis (hazard ratio [HR] 2.112, 95 % confidence interval [CI] 1.334-3.343, p = 0.001), previous HER2-TKI treatment (HR 2.019, 95 % CI 1.133-3.597, p = 0.017) and estrogen receptor positivity (HR 0.587, 95 % CI 0.370-0.934, p = 0.024). The toxicity was tolerable, with neutropenia being the most common treatment-related grade 3/4 AE (14.9 %). CONCLUSION: Inetetamab demonstrates effectiveness with a manageable safety profile, offering a promising therapeutic option for HER2-positive breast cancer patients who have shown resistance to prior anti-HER2 treatments.
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Anticuerpos Monoclonales , Antineoplásicos , Neoplasias de la Mama , Receptor ErbB-2 , Femenino , Humanos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/secundario , Pueblos del Este de Asia , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/uso terapéutico , Resultado del Tratamiento , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Interferon and chemokine-mediated immune responses are two general antiviral programs of the innate immune system in response to viral infections and have recently emerged as important players in systemic metabolism. This study found that the chemokine CCL4 is negatively regulated by glucose metabolism and avian leukosis virus subgroup J (ALV-J) infection in chicken macrophages. Low expression levels of CCL4 define this immune response to high glucose treatment or ALV-J infection. Moreover, the ALV-J envelope protein is responsible for CCL4 inhibition. We confirmed that CCL4 could inhibit glucose metabolism and ALV-J replication in chicken macrophages. The present study provides novel insights into the antiviral defense mechanism and metabolic regulation of the chemokine CCL4 in chicken macrophages.
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Endogenous retroviruses (ERVs) are remnants of the historical retroviral infections, and their derived transcripts with viral signatures are important sources of long noncoding RNAs (lncRNAs). We have previously shown that the chicken ERV-derived lncRNA lnc-ALVE1-AS1 exerts antiviral innate immunity in chicken embryo fibroblasts. However, it is not clear whether this endogenous retroviral RNA has a similar function in immune cells. Here, we found that lnc-ALVE1-AS1 was persistently inhibited in chicken macrophages after avian leukosis virus subgroup J (ALV-J) infection. Furthermore, overexpression of lnc-ALVE1-AS1 significantly inhibited the replication of exogenous ALV-J, whereas knockdown of lnc-ALVE1-AS1 promoted the replication of ALV-J in chicken macrophages. This phenomenon is attributed to the induction of antiviral innate immunity by lnc-ALVE1-AS1 in macrophages, whereas knockdown of lnc-ALVE1-AS1 had the opposite effect. Mechanistically, lnc-ALVE1-AS1 can be sensed by the cytosolic pattern recognition receptor TLR3 and trigger the type I interferons response. The present study provides novel insights into the antiviral defense of ERV-derived lncRNAs in macrophages and offers new strategies for future antiviral solutions.
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Virus de la Leucosis Aviar , ARN Largo no Codificante , Embrión de Pollo , Animales , Pollos , Virus de la Leucosis Aviar/genética , Receptor Toll-Like 3/genética , ARN Largo no Codificante/genética , Línea Celular , Macrófagos , AntiviralesRESUMEN
Utilizing Visualization-oriented Natural Language Interfaces (V-NLI) as a complementary input modality to direct manipulation for visual analytics can provide an engaging user experience. It enables users to focus on their tasks rather than having to worry about how to operate visualization tools on the interface. In the past two decades, leveraging advanced natural language processing technologies, numerous V-NLI systems have been developed in academic research and commercial software, especially in recent years. In this article, we conduct a comprehensive review of the existing V-NLIs. In order to classify each article, we develop categorical dimensions based on a classic information visualization pipeline with the extension of a V-NLI layer. The following seven stages are used: query interpretation, data transformation, visual mapping, view transformation, human interaction, dialogue management, and presentation. Finally, we also shed light on several promising directions for future work in the V-NLI community.
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Endogenous retrovirus (ERV) research amalgamates host-retroviral coevolutionary, phylogenomic, infection, immunity, and cellular studies in various hosts ranging from fish to humans. Henceforth, a bibliometric analysis of these publications may aid in the identification of trends in ERV research. It was the foremost bibliographic study, with the key aim to conduct the bibliometric network analysis (e.g. co-authorship, co-occurrence, citation, bibliographic coupling, and co-citation analysis) to find the most prolific authors, organizations, and countries in ERV research, based on the mapping of bibliographic data. Second, the mapping based on text data comprised to chalk out the research trend over the time. The global literature about endogenous retroviruses published between 1985 and Sep 2021 was searched in the Web of Science (Core Collection) database using the "ENDOGENOUS RETROVIRUS" keyword. The bibliometric analysis of this dataset was carried out using VOSviewer version 1.6.17. According to findings, English was the de facto language of these publications, and 2157 were original articles. Among 2939 published documents, "endogenous retrovirus" was the most frequent keyword. Moreover, it revealed the United States as a core contributor to studies on the ERV. The Journal of Virology published a substantial amount of manuscripts in ERV. Robert Koch Institute and Harvard University were leading organizations for research in this field. The application of ERV research from China could be the research hotspot to follow in the coming years. Current bibliometric analysis provides a comprehensive picture of ERV research progress and has highlighted the contribution of different stakeholders.
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Avian leukosis virus (ALV) has a tremendous adverse impact on the poultry industry. Since its discovery, research on different aspects of ALV have been published. Due to the vast academic emphasis and economic importance of the ALV infection in poultry worldwide, this bibliometric analysis explored the scientific output associated with ALV utilizing the Web of Science (Core Collection) database. The relevant data were collected using the search query "AVIAN LEUKOSIS VIRUS", further refined by document types (article, book chapter, and proceedings paper). Finally, 1060 items with full records were imported in Plaintext and tab-delimited formats. The data analysis was carried out using MS Excel, VOS viewer, and R (Biblioshiny) software. Chinese and American research institutions produced the majority of papers during study time period. The Journal of Virology and Avian Diseases appeared as the favorite journal/source for publications. Apart from the avian leukosis virus and the ALV-J, the important keywords mentioned included avian leukosis virus subgroup j, chicken, and retrovirus. The analysis revealed substantial findings on ALV research, with a strong research response from the USA and China.
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Nutrition and energy are essential for poultry growth and production performance. Fasting and refeeding have been widely used to study the effects of nutrition, energy, and related mechanisms in chicken. Previous studies have shown that geese have a strong capacity for fat synthesis and storage; thus, changes in the goose liver transcriptome may be different from those in chicken assessed with a model of fasting and refeeding. However, the responses of the goose liver transcriptome to fasting and refeeding have not yet been addressed. In this study, 36 70-day-old Si Ji geese with similar body weight were randomly assigned to three groups: control (ad libitum feeding), fasting (fasted for 24 h), and refeeding (fast for 24 h followed by 2-h feeding) groups. After treatment, eight geese per group were sacrificed for sample collection. Liver samples from four geese in each group were subjected to transcriptome analysis, followed by validation of differentially expressed genes (DEGs) using quantitative polymerase chain reaction with the remaining samples. As a result, 155 DEGs (73 up-regulated) were identified between the control and fasting groups, and 651 DEGs (321 up-regulated) were identified between the fasting and refeeding groups. The enrichment analyses of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed that fasting mainly influenced material metabolism in the liver, especially lipid metabolism; in contrast, refeeding affected not only lipid metabolism but also glucose and amino acid metabolism. In addition, the peroxisome proliferator-activated receptor (PPAR) signaling pathway may play an important role in lipid metabolism. In conclusion, fasting and refeeding have a strong effect on lipid metabolism in the goose liver; specifically, fasting promotes fatty acid oxidation and inhibits fatty acid synthesis, and refeeding has the opposite effect. The model of fasting and refeeding is suitable for goose nutrition studies.
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Communication between tissues and organs plays an important role in the maintenance of normal physiological functions as well as the occurrence and development of diseases. Communication molecules act as a bridge for interactions between tissues and organs, playing not only a local role in the tissues and organs where they are secreted but also in exerting systemic effects on the whole body via circulation. In this study, blood microRNA-omics analysis of overfed vs. normally fed (control) Landes geese revealed that the content of each of the 21 microRNAs (miRNAs) in the blood of overfed geese was significantly higher than that in the blood of control geese. These miRNAs may have systematic effects in the development of goose fatty liver as well as being candidate markers for the diagnosis of goose fatty liver. We determined the expression of miR-143, miR-455-5p, miR-222a-5p, miR-184, miR-1662, and miR-129-5p using quantitative PCR in goose fatty liver vs. that in normal liver. The expression of these miRNAs, except miR-129-5p, in goose fatty liver was also significantly higher than that in normal liver (P<0.05), suggesting that these blood miRNAs are released from goose fatty liver. In addition, we found that expression of IGFBP5, the predicted target gene of miR-143, was significantly decreased in goose fatty liver vs. the normal liver (P<0.05), indicating that miR-143 may exert both local and systematic effects by inhibiting the expression of IGFBP5, thus promoting the development of goose fatty liver. In conclusion, we identified several miRNAs, including those we validated (i.e., miR-143, miR-455-5p, miR-222a-5p, miR-184, miR-1662, and miR-129-5p) that may serve as candidate markers in the diagnosis of goose fatty liver as well as local and global regulators contributing to the development of goose fatty liver.
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Infection with the avian leukosis virus subgroup J (ALV-J) impairs host genes and facilitates the establishment of chronic infection and the viral life cycle. However, the involvement of long noncoding RNAs (lncRNAs) in ALV-J infection remains largely unknown. In this study, we identified a novel chicken lncRNA derived from LTR5B of the ERV-L family (namely lnc-LTR5B), which is significantly downregulated in ALV-J infected cells. lnc-LTR5B was localized in the cytoplasm and was relatively high expressed in the chicken lung and liver. Notably, the replication of ALV-J was inhibited by the overexpression of lnc-LTR5B but enhanced when lnc-LTR5B expression was knocked down. We further confirmed that lnc-LTR5B could bind to the binding immunoglobulin protein (BiP), a master regulator of endoplasmic reticulum (ER) function. Mechanistically, lnc-LTR5B serves as a competing endogenous RNA for BiP, restricting its physical availability. Upon ALV-J infection, the reduction of lnc-LTR5B released BiP, which facilitated its translocation to the cell surface. This is crucial for ALV-J entry as well as pro-survival signaling. In conclusion, we identified an endogenous retroviral LTR-activated lnc-LTR5B that is involved in regulating the cell surface translocation of BiP, and such regulatory machinery can be exploited by ALV-J to complete its life cycle and propagate.
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Metformin is a widely used antidiabetic drug for the treatment of type 2 diabetes and has been recently demonstrated to possess anti-inflammatory properties via AMPK-mediated modulation of M2 macrophage activation. However, the anti-inflammatory mechanisms of metformin on inflammatory macrophages are still not fully elucidated. In this study, we found that metformin induced apoptosis in macrophages. In particular, metformin induced apoptosis of M1 macrophages, based on M1 marker genes in apoptotic macrophages. Next, we comprehensively screened metformin-responsive genes in macrophages by RNA-seq and focused on the extrinsic apoptotic signaling pathway. The G0/G1 switch 2 gene (G0S2) was robustly up-regulated by metformin in macrophages. Overexpression of G0S2 significantly induced apoptosis of macrophages in a dose-dependent manner and blunted the function of the crucial anti-apoptotic gene Bcl-2, which was significantly reduced by metformin. These findings show that metformin promoted apoptosis of macrophages, especially M1 macrophages, via G0S2 induction and provides a novel anti-inflammatory mechanism of metformin through induction of macrophage apoptosis.
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Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Regulación de la Expresión Génica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Metformina/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Apoptosis/genética , Línea Celular , Pollos , Relación Dosis-Respuesta a Droga , Macrófagos/fisiología , Metformina/administración & dosificación , Ratones , Células RAW 264.7RESUMEN
It is known that nutrition and immunity are connected, but the mechanism is not very clear. Endogenous retroviruses (ERV) account for 8 to 10% of the human and mouse genomes and play an important role in some biological processes of animals. Recent studies indicate that the activation of ERV can affect the expression of the immunity- or inflammation-related genes, and the activities of ERV are subjected to regulation of many factors including nutritional factors. Therefore, we hypothesize that nutritional status can affect the expression of the immunity- or inflammation-related genes via ERV. To verify this hypothesis, the nutritional status of animals was altered by fasting or overfeeding, and the expression of intact ERV (ERVK18P, ERVK25P) and immunity- or inflammation-related genes (DDX41, IFIH1, IFNG, IRF7, STAT3) in the liver was determined by quantitative PCR, followed by overexpressing ERVK25P in goose primary hepatocytes and determining the expression of the immunity- or inflammation-related genes. The data showed that compared with the control group (no fasting), the expression of ERV and the immunity- or inflammation-related genes was increased in the liver of the fasted chickens but decreased in the liver of the fasted geese. Moreover, compared with the control group (routinely fed), the expression of ERV and the immunity- or inflammation-related genes was increased in the liver of the overfed geese. In addition, overexpression of ERVK25P in goose primary hepatocytes can induce the expression of the immunity- or inflammation-related genes. In conclusion, these findings suggest that ERV mediate the effects of fasting and overfeeding on the expression of the immunity- or inflammation-related genes, the mediation varied with poultry species, and ERV and the immunity- or inflammation-related genes may be involved in the development of goose fatty liver. This study provides a potential mechanism for the connection between nutrition and immunity.
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Retrovirus Endógenos/fisiología , Ayuno/fisiología , Hiperfagia/genética , Aves de Corral/genética , Animales , Pollos , Hiperfagia/inmunología , Hiperfagia/patología , Inmunidad/fisiología , Inflamación/genética , Inflamación/veterinaria , Hígado/inmunología , Hígado/patología , Ratones , Aves de Corral/inmunologíaRESUMEN
Avian leukosis virus subgroup J (ALV-J), an oncogenic retrovirus, is known to cause immunosuppression and various types of cancer in chickens. Recent reports have shown that epigenetic changes in DNA and chromatin are widely implicated in the life cycle of diverse viruses, and reversal of these changes in host cells can lead to alterations in the propagation of viruses. In the present study, we found that disruptor of telomeric silencing 1-like (DOT1L), a histone H3 lysine79 (H3K79) methyltransferase, was upregulated during ALV-J infection in chicken macrophage HD11 cells. Subsequently, we show that targeting DOT1L with a specific inhibitor can significantly decrease the ALV-J replication and viral production. By generating of DOT1L-knockout (KO) HD11 cells using the CRISPR/Cas9 system, we show that deletion of the DOT1L led to an increase in the induction of IFNß and interferon-stimulated genes (ISGs) in HD11 cells in response to ALV-J infection. Importantly, we confirmed that ALV-J infection impaired the activation of the melanoma differentiation-associated protein 5 (MDA5)-mediated-IFN pathway by suppressing the MDA5 expression, and knockout DOT1L rescued the expression of MDA5 and signal transducer and activator of transcription 1 (STAT1), both of which tightly control the antiviral innate immunity. Collectively, it can be deduced from the current data that blocking DOT1L activity or deletion of DOT1L can lead to ALV-J replication inhibition and restoration of the virally suppressed host innate immunity. Thus, we suggest that DOT1L might be a potential drug target for modulating host innate immune responses to combat ALV-J infection.
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RNA methylation is an important epigenetic modification. Recent studies on RNA methylation mainly focus on the m6A modification of mRNA, but very little is known about the m5C modification. NSUN2 is an RNA methyltransferase responsible for the m5C modification of multiple RNAs. In this study, we knocked down the NSUN2 gene in HepG2 cells by CRISPR/Cas9 technology and performed high-throughput RNA-BisSeq. An important tumor-related lncRNA H19 was identified to be targeted by NSUN2. Studies have shown that the expression of H19 lncRNA is abnormally elevated and has a carcinogenic effect in many types of tumors. Our results demonstrated that m5C modification of H19 lncRNA can increase its stability. Interestingly, m5C-modified H19 lncRNA can be specifically bound by G3BP1, a well-known oncoprotein which further leads to MYC accumulation. This may be a novel mechanism by which lncRNA H19 exerts its oncogenic effect. Besides, both the m5C methylation level and the expression level of H19 lncRNA in hepatocellular carcinoma tissues were significantly higher than those in adjacent non-cancer tissues, which were closely associated with poor differentiation of hepatocellular carcinoma (HCC). In conclusion, we found that H19 RNA is a specific target for the NSUN2 modifier. The m5C-modified H19 lncRNA may promote the occurrence and development of tumors by recruiting the G3BP1 oncoprotein. Our findings may provide a potential target and biomarker for the diagnosis and treatment of HCC.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Metiltransferasas/metabolismo , ARN Largo no Codificante/metabolismo , 5-Metilcitosina/metabolismo , Animales , Carcinoma Hepatocelular/patología , Diferenciación Celular/genética , ADN Helicasas/metabolismo , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células Hep G2 , Humanos , Hígado/patología , Neoplasias Hepáticas/patología , Masculino , Metilación , Metiltransferasas/genética , Ratones , Persona de Mediana Edad , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , RNA-Seq , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The survival status of patients with breast cancer and brain metastasis (BCBM) receiving current treatments is poor. METHOD: We designed a real-world study to investigate using patients' clinical and genetic aberrations to forecast the prognoses of BCBM patients. We recruited 146 BCBM patients and analyzed their clinical features to evaluate the overall survival (OS). For genetic testing, 30 BCBM and 165 non-brain-metastatic (BM) metastatic breast cancer (MBC) patients from Hunan Cancer Hospital, and 86 BCBM and 1416 non-BM MBC patients from the Geneplus database who received circulating tumor DNA testing, were compared and analyzed. RESULTS: Ki67 >14% and >3 metastatic brain tumors were significant risk factors associated with poor OS, while chemotherapy and brain radiotherapy were beneficial factors for better OS. Compared with non-BM MBC patients, BCBM patients had more fibroblast growth factor receptor (FGFR) aberrations. The combination of FGFR, TP53 and FLT1 aberrations plus immunohistochemistry HER2-positive were associated with an increased risk of brain metastasis (AUC = 77.13%). FGFR aberration alone was not only a predictive factor (AUC = 67.90%), but also a significant risk factor for poor progression-free survival (Logrank p = 0.029). FGFR1 aberration was more frequent than other FGFR family genes in BCBM patients, and FGFR1 aberration was significantly higher in BCBM patients than non-BM MBC patients. Most FGFR1-amplified MBC patients progressed within 3 months of the late-line (>2 lines) treatment. CONCLUSION: A group of genetic events, including FGFR, TP53 and FLT1 genetic aberrations, and HER2-positivity, forecasted the occurrence of BM in breast cancers. FGFR genetic aberration alone predicted poor prognosis.
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This study aims to detect the prognostic value of circulating tumour cell (CTC) in patients with metastatic breast cancer. In this study, 38 patients with metastatic breast cancer were enrolled. The in vivo CellCollector® method was used to detect the number of CTC in patients. Single CTC and CTC clusters were counted, and the expression of plakoglobin was also analysed. At baseline, 73.7% (28/38) of the patients were positive for ≥ 1 CTC (range, 1-14 cells). No CTC-like events were observed in the control group. Among the CTC-positive patients, 21.4% (6/28) of patients had CTC clusters, and 42.9% (12/28) of patients had plakoglobin-positive CTC. After chemotherapy, 48.6% (17/35) of the patients were positive for ≥ 1 CTC (range, 1-3 cells), of which 3 patients had CTC clusters, and 35.3% (6/17) had plakoglobin-positive CTC. Additionally, we found that the number of CTC clusters in plakoglobin-positive patients was much greater than that in plakoglobin-negative patients, and the number of CTC was associated with the number of sites of metastases. We also found that patients with ≥ 3 CTC at baseline had shorter progression-free survival (PFS) and overall survival (OS), and pre-chemotherapy CTC detection was associated with PFS (P = 0.0001) and OS (P = 0.0091). CTC plakoglobin expression was associated with PFS (P = 0.02) but not OS (P = 0.22). CTC collected by the in vivo CellCollector method in Chinese patients with metastatic breast cancer have prognostic significance. CTC plakoglobin expression may be associated with CTC clusters, and more in-depth studies are needed.
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Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Células Neoplásicas Circulantes/patología , Adulto , Anciano , Separación Celular , Femenino , Humanos , Persona de Mediana Edad , Células Neoplásicas Circulantes/metabolismo , Pronóstico , gamma Catenina/metabolismoRESUMEN
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease characterized by persistent anovulation and hyperandrogenism, affecting approximately 8-10% of women of childbearing age and occupying an important position in the etiology of infertility. There is increasing evidence that long non-coding RNAs (lncRNAs) are involved in the development of PCOS, but the potential regulatory mechanism is still unclear. This study performed high-throughput lncRNA sequencing of follicular fluid exosomes in non-PCOS infertility patients and PCOS infertility patients. The sequencing results led to the identification of 1,253 upregulated and 613 downregulated lncRNAs from a total of 1,866 detected candidates. There was no significant difference between the PCOS patients and non-PCOS patients in body mass index (BMI) or the fasting blood glucose (FBG) level. However, luteinizing hormone (LH), estradiol (E2), testosterone (T), serum prolactin (PRL), and anti-Mullerian hormone (AMH) levels were clearly upregulated in PCOS patients compared to those in non-PCOS patients. There was also an increase in LH/FSH (>2) in the PCOS patients. Functional analysis showed pathways related to endocytosis, the Hippo, the MAPK, and HTLV-1 infection. These results suggest that lncRNAs may play an important role in the pathogenesis of PCOS and may be potential targets for the diagnosis and treatment of PCOS.
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Human TRDMT1 is a transfer RNA (tRNA) methyltransferase for cytosine-5 methylation and has been suggested to be involved in the regulation of numerous developmental processes. However, little is known about the molecular mechanisms or their biological significance. In this study, we investigated the effects of CRISPR-based TRDMT1 knockdown on phenotypes, mRNA m5C modifications and gene expression changes in HEK293â¯cells. We found that knockdown of TRDMT1 significantly inhibited cell proliferation and migration but had no effect on clonogenic potential. The inhibitory effects could be attenuated by re-expression of TRDMT1 in HEK293â¯cells. RNA sequencing (RNA-Seq) and RNA bisulfite sequencing (RNA-BisSeq) were performed in TRDMT1 knockdown and wild-type HEK293â¯cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that the differentially expressed genes were associated with the cell cycle, RNA transport, and RNA degradation and were enriched in cancer and Notch signaling pathways. We also found that TRDMT1 knockdown could change mRNA methylation levels. For the first time, these findings clarify the role of TRDMT1 in regulating mRNA methylation and inhibiting the proliferation and migration of HEK293â¯cells. These results provide new insights into a new function of TRDMT1 and elucidate the molecular mechanisms of aberrant RNA m5C during tumorigenesis.
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5-Metilcitosina/metabolismo , Movimiento Celular , Proliferación Celular , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ARN Mensajero/metabolismo , Sistemas CRISPR-Cas , Carcinogénesis , Biología Computacional , Metilación de ADN , Perfilación de la Expresión Génica , Células HEK293 , Humanos , Fenotipo , RNA-Seq , Transducción de SeñalRESUMEN
Endogenous retroviruses (ERVs) constitute an important component of animal and human genomes and are usually silenced by epigenetic mechanisms in adult cells. Although ERVs were recently reported to be linked to early development, tumorigenesis and autoimmune disease, their impacts on antiviral innate immunity and the underlying mechanisms have not been elucidated. Here, we provide the first direct evidence of an endogenous retroviral element affecting antiviral innate immunity via its derived antisense long non-coding RNA (lncRNA). We found that an antisense lncRNA, which is called lnc-ALVE1-AS1 and is transcribed from the endogenous avian leukosis virus in chromosome 1 (ALVE1), distinctly inhibited the entry and replication of exogenous retroviruses in chicken embryonic fibroblasts (CEFs). This behaviour is at least in part attributed to the induction of an antiviral innate immune pathway by ALVE1 activation, suggesting that an activated endogenous retroviral element may induce antiviral defence responses via its derived antisense lncRNA. We also found that lnc-ALVE1-AS1 mediated these effects by activating the TLR3 signalling in the cytoplasm. Our results provide novel insights into the antiviral innate immune function of ERVs, suggesting that ERVs may play an important role in antiviral defences and provide new strategies for the development of new vaccines.