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BACKGROUND AND PURPOSE: The PARP inhibitor (PARPi), Talazoparib (BMN673), effectively and specifically radiosensitizes cancer cells. Radiosensitization is mediated by a shift in the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) toward PARP1-independent, alternative end-joining (alt-EJ). DNA polymerase theta (Polθ) is a key component of this PARP1-independent alt-EJ pathway and we show here that its inhibition can further radiosensitize talazoparib-treated cells. The purpose of the present work is to explore mechanisms and dynamics underpinning enhanced talazoparib radiosensitization by Polθ inhibitors in HR-proficient cancer cells. METHODS AND MATERIALS: Radiosensitization to PARPis, talazoparib, olaparib, rucaparib and veliparib was assessed by clonogenic survival. Polθ-proficient and -deficient cells were treated with PARPis and/or with the Polθ inhibitors ART558 or novobiocin. The role of DNA end-resection was studied by down-regulating CtIP and MRE11 expression using siRNAs. DSB repair was assessed by scoring γH2AX foci. The formation of chromosomal abnormalities was assessed as evidence of alt-EJ function using G2-specific cytogenetic analysis. RESULTS: Talazoparib exerted pronounced radiosensitization that varied among the tested cancer cell lines; however, radiosensitization was undetectable in normal cells. Other commonly used PARPis, olaparib, veliparib, or rucaparib were ineffective radiosensitizers under our experimental conditions. Although genetic ablation or pharmacological inhibition of Polθ only mildly radiosensitized cancer cells, talazoparib-treated cells were markedly further radiosensitized. Mechanistically, talazoparib shunted DSBs to Polθ-dependent alt-EJ by enhancing DNA end-resection in a CtIP- and MRE11-dependent manner - an effect detectable at low, but not high IR doses. Chromosomal translocation analysis in talazoparib-treated cells exposed to Polθ inhibitors suggested that PARP1- and Polθ-dependent alt-EJ pathways may complement, but also back up each other. CONCLUSION: We propose that talazoparib promotes low-dose, CtIP/MRE11-dependent resection and increases the reliance of irradiated HR-proficient cancer cells, on Polθ-mediated alt-EJ. The combination of Polθ inhibitors with talazoparib suppresses this option and causes further radiosensitization. The results suggest that Polθ inhibition may be exploited to maximize talazoparib radiosensitization of HR-proficient tumors in the clinic.
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Obese asthma is a unique asthma phenotype that decreases sensitivity to inhaled corticosteroids, and currently lacks efficient therapeutic medication. Celastrol, a powerful bioactive substance obtained naturally from the roots of Tripterygium wilfordii, has been reported to possess the potential effect of weight loss in obese individuals. However, its role in the treatment of obese asthma is not fully elucidated. In the present study, diet-induced obesity (DIO) mice were used with or without ovalbumin (OVA) sensitization, the therapeutic effects of celastrol on airway hyperresponsiveness (AHR) and airway inflammation were examined. We found celastrol significantly decreased methacholine-induced AHR in obese asthma, as well as reducing the infiltration of inflammatory cells and goblet cell hyperplasia in the airways. This effect was likely due to the inhibition of M1-type alveolar macrophages (AMs) polarization and the promotion of M2-type macrophage polarization. In vitro, celastrol yielded equivalent outcomes in Lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells, featuring a reduction in the expression of M1 macrophage makers (iNOS, IL-1ß, TNF-α) and heightened M2 macrophage makers (Arg-1, IL-10). Mechanistically, the PI3K/AKT signaling pathway has been implicated in these processes. In conclusion, we demonstrated that celastrol assisted in mitigating various parameters of obese asthma by regulating the balance of M1/M2 AMs polarization.
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Asma , Macrófagos Alveolares , Obesidad , Triterpenos Pentacíclicos , Triterpenos , Animales , Asma/tratamiento farmacológico , Triterpenos Pentacíclicos/farmacología , Obesidad/tratamiento farmacológico , Obesidad/complicaciones , Ratones , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Triterpenos/farmacología , Triterpenos/uso terapéutico , Células RAW 264.7 , Inflamación/tratamiento farmacológico , Inflamación/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Hipersensibilidad Respiratoria/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones Endogámicos C57BL , Ovalbúmina , Polaridad Celular/efectos de los fármacosRESUMEN
BACKGROUND: Osteoclast plays an important role in maintaining the balance between bone anabolism and bone catabolism. The abnormality of osteoclast is closely related to osteolytic bone diseases such as osteoporosis, rheumatoid arthritis and tumor bone metastasis. PURPOSE: We aim to search for natural compound that may suppress osteoclast formation and function. STUDY DESIGN: In this study, we assessed the impact of Dauricine (Dau) on the formation and function of osteoclasts in vitro, as well as its potential in preventing bone loss in an ovariectomy mouse model in vivo. METHODS: Multiple in vitro experiments were carried out, including osteoclastogenesis, podosomal belt formation, bone resorption assay, RNA-sequencing, real-time quantitative PCR, ROS level detection, surface plasmon resonance assay, luciferase assay and western blot. To verify the effect in vivo, an ovariectomized mouse model (OVX model) was constructed, and bone parameters were measured using micro-CT and histology. Furthermore, metabolomics analysis was performed on blood serum samples from the OVX model. RESULTS: In vitro experiments demonstrated that Dau inhibits RANKL-induced osteoclastogenesis, podosomal belt formation, and bone resorption function. RNA-sequencing results revealed that Dau significantly suppresses genes related to osteoclast. Functional enrichment analysis indicated that Dau's inhibition of osteoclasts may be associated with NF-κB signaling pathway and reactive oxygen metabolism pathway. Molecular docking, surface plasmon resonance assay and western blot analysis further confirmed that Dau inhibits RANKL-induced osteoclastogenesis by modulating the ROS/NF-κB/NFATc1 pathway. Moreover, administration of Dau to OVX-induced mice validated its efficacy in treating bone loss disease. CONCLUSION: Dau prevents OVX-induced bone loss by inhibiting osteoclast activity and bone resorption, potentially offering a new approach for preventing and treating metabolic bone diseases such as osteoporosis. This study provides innovative insights into the inhibitory effects of Dau in an in vivo OVX model and elucidates the underlying mechanism.
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Bencilisoquinolinas , FN-kappa B , Factores de Transcripción NFATC , Osteoclastos , Osteogénesis , Ovariectomía , Ligando RANK , Especies Reactivas de Oxígeno , Animales , Bencilisoquinolinas/farmacología , Femenino , Ligando RANK/metabolismo , Ratones , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Osteogénesis/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Modelos Animales de Enfermedad , Resorción Ósea/tratamiento farmacológico , Ratones Endogámicos C57BL , Células RAW 264.7 , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Humanos , TetrahidroisoquinolinasRESUMEN
Tissue-resident stem cells are essential for development and repair, and in the skeleton, this function is fulfilled by recently identified skeletal stem cells (SSCs). However, recent work has identified that SSCs are not monolithic, with long bones, craniofacial sites, and the spine being formed by distinct stem cells. Recent studies have utilized techniques such as fluorescence-activated cell sorting, lineage tracing, and single-cell sequencing to investigate the involvement of SSCs in bone development, homeostasis, and disease. These investigations have allowed researchers to map the lineage commitment trajectory of SSCs in different parts of the body and at different time points. Furthermore, recent studies have shed light on the characteristics of SSCs in both physiological and pathological conditions. This review focuses on discussing the spatiotemporal distribution of SSCs and enhancing our understanding of the diversity and plasticity of SSCs by summarizing recent discoveries.
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Desarrollo Óseo , Homeostasis , Células Madre , Humanos , Animales , Células Madre/citología , Células Madre/metabolismo , Huesos/citología , Huesos/metabolismoRESUMEN
Innate lymphoid cells (ILCs) are the most recently identified immune cell types existing in lymphoid and nonlymphoid organs. Albeit they lack the expression of antigen receptors, ILCs play vital roles in innate immune responses by producing multiple effector cytokines. The ILC family includes conventional natural killer cells and cytokine-producing ILCs, which are divided into group 1, group 2, and group 3 ILCs based on their effector cytokines and developmental requirements. Emerging evidence has indicated that ILCs are essential immune regulators of bone homeostasis, playing a critical role in osteoimmunology. In this mini-review, we discuss recent advances in the understanding of ILC functions in bone homeostasis under physiological and pathological conditions, with an emphasis on the communication between ILCs and bone cells including osteoclasts and osteoblasts, as well as the underlying immunoregulatory networks involving ILC-derived cytokines and growth factors. This review also discusses future research directions and the potential of targeting ILCs for the treatment of inflammation-associated bone disorders.
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Inmunidad Innata , Linfocitos , Citocinas/metabolismo , Células Asesinas NaturalesRESUMEN
Obesityincreasestheriskofasthma and tends to enhance the asthma severity, however, its mechanism is not fully elucidated. The expansion of adipose tissue in obesity is accompanied by the accumulation of adiposetissue macrophages (ATMs) that could contribute to alow-gradeinflammationstate. In this study, we researched the regulatory role of soluble epoxide hydrolase (sEH) on ATMs-mediated inflammation in obese asthma. A mouse model of obese asthma that induced by high-fat diet (HFD) feeding and Ovalbumin (OVA) sensitization was employed to investigate the effects of AUDA, a sEH inhibitor (sEHi), on airway inflammation, airway hyperresponsivenesss (AHR) and pulmonary pathological changes. In addition to alleviating the key features of asthma in obese mice, we confirmed that AUDA reduced the expression of pro-inflammatory factor, such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumornecrosisfactor-α (TNF-α) in adipose tissue and serum. Moreover, AUDA could remarkedly reduce Lipopolysaccharide (LPS)-elevated IL-1ß, IL-6 and TNF-α in RAW264.7 macrophage cells. Mechanistically, AUDA effectively reduced inflammation in adipose tissue, resulting in reduced systemic inflammation, by inhibiting M1-type macrophage polarization and promoting M2-type macrophage polarization. These processes were found to act through ERK1/2 signaling pathway. Herein, we proved that inhibition of sEH expression helped to mitigate multiple parameters of obese asthma by regulating the balance of M1/M2 macrophage polarization in adipose tissue.
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Asma , Epóxido Hidrolasas , Animales , Ratones , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Inflamación/metabolismo , Obesidad/metabolismo , Asma/tratamiento farmacológico , Asma/metabolismo , Macrófagos , Tejido Adiposo/metabolismo , Ratones Endogámicos C57BLRESUMEN
The most common site of metastasis in breast cancer is the bone, where the balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation is disrupted. This imbalance causes osteolytic bone metastasis in breast cancer, which leads to bone pain, pathological fractures, spinal cord compression, and other skeletal-related events (SREs). These complications reduce patients' quality of life significantly and have a profound impact on prognosis. In this review, we begin by providing a brief overview of the epidemiology of bone metastasis in breast cancer, including current diagnostic tools, treatment approaches, and existing challenges. Then, we will introduce the pathophysiology of breast cancer bone metastasis (BCBM) and the animal models involved in the study of BCBM. We then come to the focus of this paper: a discussion of several biomarkers that have the potential to provide predictive and prognostic value in the context of BCBM-some of which may be particularly compatible with more comprehensive liquid biopsies. Beyond that, we briefly explore the potential of new technologies such as single-cell sequencing and organoid models, which will improve our understanding of tumor heterogeneity and aid in the development of improved biomarkers. The emerging biomarkers discussed hold promise for future clinical application, aiding in the prevention of BCBM, improving the prognosis of patients, and guiding the implementation of personalized medicine.
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Background: Breast cancer (BC) is the leading cause of death in the female reproductive system, often linked to lymph node involvement, indicating poor prognosis. This study investigated lymph node metastasis incidence and risk factors in M0 stage BC patients who hadn't received preoperative chemoradiotherapy or neoadjuvant therapy. We explored the influence of various factors on lymph node metastasis. Methods: We conducted a retrospective analysis using Surveillance, Epidemiology, and End Results data from BC patients diagnosed between 2010 and 2015. Binary logistic regression and propensity score matching (PSM) assessed significant factors in BC patients without preoperative treatment. We developed predictive nomograms and evaluated model performance using the concordance index, calibration curve, area under the curve, and decision curve analysis. Results: Among 256,504 eligible BC patients, 25.57% had lymph node metastasis. Multivariate logistic regression revealed associations between lymph node metastasis and younger age, African-American ethnicity, central/nipple location, lobular carcinoma, human epidermal growth factor receptor 2 (HER2)-positive status, grade III classification, and T3 stage. PSM confirmed these findings. Interactions were identified between age, race, primary site, histology, breast subtype, grade, and T stage, all influencing lymph node metastasis. Conclusions: This retrospective study identified lymph node metastasis in female BC patients with distinct clinicopathological characteristics who received no preoperative treatment. We constructed valuable nomograms, revealing that: (I) young age (<35 years), African-American race, central/nipple location, infiltrating duct carcinoma, HER2 positivity, high histological grade (grade III), and larger tumor size are risk factors for regional lymph node metastasis; (II) lymph node metastasis may not solely represent the invasive nature of triple-negative BC; (III) patients with different BC subtypes in T1c-T2 stages may benefit from individualized neoadjuvant treatment strategies.
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Background: Skin cutaneous melanoma is characterized by high malignancy and prognostic heterogeneity. Immune cell networks are critical to the biological progression of melanoma through the tumor microenvironment. Thus, identifying effective biomarkers for skin cutaneous melanoma from the perspective of the tumor microenvironment may offer strategies for precise prognosis prediction and treatment selection. Methods: A total of 470 cases from The Cancer Genome Atlas and 214 from the Gene Expression Omnibus were systematically evaluated to construct an optimal independent immune cell risk model with predictive value using weighted gene co-expression network analysis, Cox regression, and least absolute shrinkage and selection operator assay. The predictive power of the developed model was estimated through receiver operating characteristic curves and Kaplan-Meier analysis. The association of the model with tumor microenvironment status, immune checkpoints, and mutation burden was assessed using multiple algorithms. Additionally, the sensitivity of immune and chemotherapeutics was evaluated using the ImmunophenScore and pRRophetic algorithm. Furthermore, the expression profiles of risk genes were validated using gene expression profiling interactive analysis and Human Protein Atlas resources. Results: The risk model integrated seven immune-related genes: ARNTL, N4BP2L1, PARP11, NUB1, GSDMD, HAPLN3, and IRX3. The model demonstrated considerable predictive ability and was positively associated with clinical and molecular characteristics. It can be utilized as a prognostic factor for skin cutaneous melanoma, where a high-risk score was linked to a poor prognosis and indicated an immunosuppressive microenvironment. Furthermore, the model revealed several potential target checkpoints and predicted the therapeutic benefits of multiple clinically used drugs. Conclusion: Our findings provide a comprehensive landscape of the tumor immune microenvironment in skin cutaneous melanoma and identify prognostic markers that may serve as efficient clinical diagnosis and treatment selection tools.
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Purpose: Recent studies had shown that gut microbiota played a significant role in the development of the immune system and may affect the course of airway allergic disease. We conducted this study to determine unique gut microbial associated with allergic disease in children by shotgun gene sequencing. Methods: We collected fecal samples from children with allergic asthma (n = 23) and allergic rhinitis (n = 18), and healthy control (n = 19). The gut microbiota of specimens was analyzed by high-throughput metagenomic shotgun gene sequencing. Results: The intestinal microbiota of children with allergic asthma and allergic rhinitis was characterized by increased microbial richness and diversity. Simpson and Shannon were significantly elevated in children with allergic asthma. Principal coordinates analysis (PCoA) showed that the gut microbial communities cluster patterns of children with asthma or rhinitis were significantly different from those of healthy controls. However, no significant difference was found between asthma group and rhinitis group At the phylum level, higher relative abundance of Firmicutes was found in the allergic rhinitis group and allergic asthma group, while the level of Bacteroidetes was significantly lower. At the genus level, Corynebacterium, Streptococcus, Dorea, Actinomyces, Bifidobacterium, Blautia, and Rothia were significantly enriched in the allergic asthma group. Finally, a random forest classifier model selected 16 general signatures to discriminate the allergic asthma group from the healthy control group. Conclusion: In conclusion, children in the allergic rhinitis group and allergic asthma group had altered gut microbiomes in comparison with the healthy control group. Compared to healthy children, the gut microbiome in children with allergic diseases has higher pro-inflammatory potential and increased production of pro-inflammatory molecules.
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Obesity increases the severity of airway hyperresponsiveness (AHR) in individuals with asthma, but the mechanism is not well elucidated. G-protein coupled receptor 40 (GPR40) has been found to induce airway smooth muscle contraction after activated by long-chain fatty acids (LC-FFAs), suggesting a close correlation between GPR40 and AHR in obese. In this study, C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity with or without ovalbumin (OVA) sensitization, the regulatory effects of GPR40 on AHR, inflammatory cells infiltration, and the expression of Th1/Th2 cytokines were evaluated by using a small-molecule antagonist of GPR40, DC260126. We found that the free fatty acids (FFAs) level and GPR40 expression were greatly elevated in the pulmonary tissues of obese asthmatic mice. DC260126 greatly reduced methacholine-induced AHR, ameliorated pulmonary pathological changes and decreased inflammatory cell infiltration in the airways in obese asthma. In addition, DC260126 could down-regulate the levels of Th2 cytokines (IL-4, IL-5, and IL-13) and pro-inflammatory cytokines (IL-1ß, TNF-α), but elevated Th1 cytokine (IFN-γ) expression. In vitro, DC260126 could remarkedly reduce oleic acid (OA)-induced cell proliferation and migration in HASM cells. Mechanistically, the effects that DC260126 alleviated obese asthma was correlated with the down-regulation of GTP-RhoA and Rho-associated coiled-coil-forming protein kinase 1 (ROCK1). Herein, we proved that targeting of GPR40 with its antagonist helped to mitigate multiple parameters of obese asthma effectively.
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Asma , Receptores Acoplados a Proteínas G , Hipersensibilidad Respiratoria , Animales , Ratones , Asma/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Pulmón/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/metabolismo , Ovalbúmina , Receptores Acoplados a Proteínas G/metabolismo , Hipersensibilidad Respiratoria/metabolismo , Transducción de SeñalRESUMEN
Osteoclast differentiation and function are critical targets for anti-osteoporosis treatment. Oxidative stress also plays an important regulatory role in the differentiation of osteoclasts. Corylifol A (CA) is a flavonoid extracted from the Psoralea fruit. It has anti-inflammatory and antioxidant properties despite its unknown effect on osteoporosis. This study found that CA prevented estrogen-deficiency-induced bone loss and suppressed osteoclastogenesis in ovariectomized (OVX) mice by inhibiting intracellular reactive oxygen species (ROS) levels. In vivo, CA effectively prevented trabecular bone loss and reduced osteoclasts' number on the bone surface in OVX mice, as demonstrated in micro-CT, osteometry, and immunohistochemical data. However, CA did not affect cortical bone. In vitro, CA inhibited RANKL-induced podosome belt formation, osteoclastogenesis, and bone resorption functions. CA suppressed RANKL-induced ROS by boosting antioxidant enzymes (Catalase and NQO1) and NFATc1 signaling pathway related protein expression, including integrin αvß3, NFATc1 and CTSK. Moreover, CA inhibited osteoclast-specific genes, including Ctsk, Acp5, and Mmp9. CA also attenuated the MAPK/ERK pathway, but did not affect the NF-κB signaling pathway. In terms of osteogenesis, CA did not inhibit or promote osteogenic differentiation and mineralization in vitro. These results reveal that CA could be a new replacement therapy for treating estrogen-deficiency osteoporosis via suppressing osteoclastogenesis and intracellular ROS.
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Resorción Ósea , Osteoporosis , Animales , Ratones , Osteogénesis , Especies Reactivas de Oxígeno/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Osteoclastos/metabolismo , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/genética , Resorción Ósea/prevención & control , Osteoporosis/tratamiento farmacológico , Osteoporosis/genética , Osteoporosis/prevención & control , FN-kappa B/metabolismo , Estrógenos/metabolismo , Ligando RANK/genética , Ligando RANK/farmacología , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Diferenciación Celular , Ratones Endogámicos C57BLRESUMEN
Allergic asthma is a chronic inflammatory disease primarily mediated by Th2 immune mechanisms. Exposure to antibiotics during early life is associated with an increased risk of allergic asthma, although the exact mechanism is not fully understood. In this study, mice were randomly divided into a normal saline control group (NS group), an OVA-induced asthma group (OVA group), a vancomycin treatment control group (VAN.NS group), and a vancomycin treatment the OVA-induced asthma group (VAN.OVA group). The results showed that vancomycin altered dominant species in experimental mice. The phylum level histogram showed that Bacteroides abundance was increased, and Firmicutes abundance was decreased in the OVA group. Airway inflammation and airway hyperresponsiveness (AHR) were aggravated in the vancomycin-exposed group. Enzyme-linked immunosorbent assay (ELISA) showed that the serum levels of IL-5, IL-13, and IL-33 in the OVA group were higher than those in the NS group, especially in the VAN.OVA group. The expression of GATA binding protein-3(GATA3) and retinoid acid receptor-related orphan receptor alpha (RORa) increased in the OVA group, even more so in the VAN.OVA group. Group 2 innate lymphoid cells (ILC2s) in the lung detected by flow cytometry was increased in OVA mice more than those in control mice, with a more remarkable increase in the VAN.OVA. Our results demonstrated that vancomycin used in early life could alter the intestinal microecology of mice, which, in turn, aggravates airway inflammation and upregulate type 2 innate lymphocytes.
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Asma , Microbioma Gastrointestinal , Ratones , Animales , Vancomicina/farmacología , Inmunidad Innata , Ovalbúmina , Linfocitos/metabolismo , Asma/inducido químicamente , Asma/tratamiento farmacológico , Pulmón/metabolismo , Inflamación/inducido químicamente , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad , Líquido del Lavado BronquioalveolarRESUMEN
BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements.
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Systemic therapy is one of the most significant cancer treatments. However, drug resistance often appears and has become the primary cause of cancer therapy failure. Regulation of drug target, drug metabolism and drug efflux, cell death escape (apoptosis, autophagy, et al.), epigenetic changes, and many other variables are complicatedly involved in the mechanisms of drug resistance. In various types of cancers, long non-coding RNA H19 (lncRNA H19) has been shown to play critical roles in tumor development, proliferation, metastasis, and multiple drug resistance as well. The efficacy of chemotherapy, endocrine therapy, and targeted therapy are all influenced by the expression of H19, especially in breast cancer, liver cancer, lung cancer and colorectal cancer. Here, we summarize the relationship between lncRNA H19 and tumorigenesis, and illustrate the drug resistance mechanisms caused by lncRNA H19 as well. This review may provide more therapeutic potential targets for future cancer treatments.
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INTRODUCTION: While breast reconstruction has become more and more important within the past decade, research focus areas as well as trends are in constant change. METHOD: The publications from 2012 to 2021 were retrieved from the Web of Science Core Collection database. CiteSpace visualization analysis software was used to analyze the institutions, countries, regions, categories, and keywords on breast reconstruction research. RESULT: A total of 3092 articles were selected. The number of articles published in the last 10 years showed an upward trend year by year. The journal "Plastic and Reconstructive Surgery" had the largest number of publications and citations, representing the core journal. The USA had the largest number of publications and the most extensive cooperation with other countries. The research highlights mainly focused on the improvement of surgical techniques, enhancing postoperative recovery, and oncological safety. CONCLUSION: Over the past decade, research on breast reconstruction has developed steadily, and considerable achievements in the field of surgical techniques, postoperative recovery, and oncological safety were reached. Plastic surgeons should continue to strive for a higher level of evidence study designs, while also recognizing the importance of international and multiple-center cooperation.
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Bibliometría , Mamoplastia , Bases de Datos Factuales , Humanos , Publicaciones , Proyectos de InvestigaciónRESUMEN
Osteoporosis is a serious public health problem that results in fragility fractures, especially in postmenopausal women. Because the current therapeutic strategy for osteoporosis has various side effects, a safer and more effective treatment is worth exploring. It is important to examine natural plant extracts during new drug design due to low toxicity. Mogrol is an aglycon of mogroside, which is the active component of Siraitia grosvenorii (Swingle) and exhibits anti-inflammatory, anticancer and neuroprotective effects. Here, we demonstrated that mogrol dose-dependently inhibited osteoclast formation and function. To confirm the mechanism, RNA sequencing (RNA-seq), real-time PCR (RT-PCR), immunofluorescence and Western blotting were performed. The RNA-seq data revealed that mogrol had an effect on genes involved in osteoclastogenesis. Furthermore, RT-PCR indicated that mogrol suppressed osteoclastogenesis-related gene expression, including CTSK, ACP5, MMP9 and DC-STAMP, in RANKL-induced bone marrow macrophages Western blotting demonstrated that mogrol suppressed osteoclast formation by blocking TNF receptor-associated factor 6 (TRAF6)-dependent activation of the mitogen-activated protein kinase nuclear factor-B (NF-κB) signaling pathway, which decreased two vital downstream transcription factors, the nuclear factor of activated T cells calcineurin-dependent 1 (NFATc1) and c-Fos proteins expression. Furthermore, mogrol dramatically reduced bone mass loss in postmenopausal mice. In conclusion, these data showed that mogrol may be a promising procedure for osteoporosis prevention or therapy.
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BACKGROUND: Ferroptosis is a special form of cell death with extensive biological associations with various cancers; however, the role of aberrantly expressed ferroptosis-related long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) remains unclear. OBJECTIVES: To explore the role and prognostic value of ferroptosis-related lncRNAs in HCC and to screen potential therapeutic targets. MATERIAL AND METHODS: The RNA-seq data for 424 HCC patients and clinical data for 377 HCC patients were obtained from The Cancer Genome Atlas (TCGA) and evaluated using the Pearson's test to identify differentially expressed lncRNAs. The univariate analysis, least absolute shrinkage and selection operator Cox regression analysis were performed to construct and validate a prognostic risk-score model. The prognostic capacity was evaluated using the Kaplan-Meier method, univariate and multivariate Cox regression, and receiver operating characteristic (ROC) curve analyses. The enrichment analysis was performed to explore the functions of ferroptosis-related lncRNAs from the perspective of tumor immunology. RESULTS: Seventeen differentially expressed lncRNAs were identified (AL139384.1, AL928654.1, MKLN1-AS, AC145207.8, LINC00205, ZFPM2-AS1, LINC00942, POLH-AS1, AC090772.3, AL603839.3, AC012073.1, AC099850.1, AC026401.3, AP001469.3, AL031985.3, SNHG10, SNHG21) to establish the risk-score model. Survival analyses demonstrated poorer survival in high-risk patients, and the risk score was shown to be a better independent prognostic factor than conventional clinical characteristics. Additionally, we found close correlations between the risk score and immune cell subpopulation functions, as well as between the expression of immune checkpoint and carcinogenic N6-methyladenosine (m6A)-related mRNAs. CONCLUSIONS: The novel ferroptosis-related lncRNA signature may serve as an individualized prognostic prediction tool for patients with HCC.
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Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , ARN Largo no Codificante/genética , Pronóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ferroptosis/genética , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/análisis , Estimación de Kaplan-MeierRESUMEN
[This corrects the article DOI: 10.3389/fphar.2019.00982.].