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Potassium ion transport across myocardial cell membrane is essential for type 2 long QT syndrome (LQT2). However, the dysfunction of potassium ion transport due to genetic mutations limits the therapeutic effect in treating LQT2. Biomimetic ion channels that selectively and efficiently transport potassium ions across the cellular membranes are promising for the treatment of LQT2. To corroborate this, we synthesized a series of foldamer-based ion channels with different side chains, and found a biomimetic ion channel of K+ (BICK) with the highest transport activity among them. The selected BICK can restore potassium ion transport and increase transmembrane potassium ion current, thus shortening phase 3 of action potential (AP) repolarization and QT interval in LQT2. Moreover, BICK does not affect heart rate and cardiac rhythm in treating LQT2 model induced by E4031 in isolated heart as well as in guinea pigs. By restoring ion transmembrane transport tactic, biomimetic ion channels, such as BICK, will show great potential in treating diseases related to ion transport blockade. STATEMENT OF SIGNIFICANCE: Type 2 long QT syndrome (LQT2) is a disease caused by K+ transport disorder, which can cause malignant arrhythmia and even death. There is currently no radical cure, so it is critical to explore ways to improve K+ transmembrane transport. In this study, we report that a small-molecule biomimetic ion channel BICK can efficiently simulate natural K+ channel proteins on the cardiomyocyte and cure E4031-induced LQT2 in guinea pig by restoring K+ transport function for the first time. This study found that the potassium transmembrane transport by BICK significantly reduced the QT interval, which provides a conceptually new strategy for the treatment of LQT2 disease.
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Síndrome do QT Longo , Potássio , Síndrome do QT Longo/metabolismo , Animais , Potássio/metabolismo , Cobaias , Humanos , Potenciais de Ação/efeitos dos fármacos , Transporte de Íons/efeitos dos fármacos , Masculino , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Canais de Potássio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Frequência Cardíaca/efeitos dos fármacosRESUMO
BACKGROUND: Immunotherapy has revolutionized cancer treatment. Recent studies have suggested that the efficacy of immunotherapy can be further enhanced by the influence of gut microbiota. In this study, we aimed to investigate the impact of bacteria on the effectiveness of cancer immunotherapy by combining analysis of clinical samples with validation in animal models. METHODS: In order to characterize the diversity and composition of microbiota and its relationship with response to immune checkpoint inhibitors (ICIs), 16S ribosomal RNA (rRNA) and GC-MS sequencing was performed on 71 stool samples from patients with advanced non-small cell lung cancer (NSCLC) prior to treatment with immune checkpoint blockade (ICB). Furthermore, fecal microbiota transplantation (FMT) was performed from different patients into mice and a subcutaneous tumor model established using the Lewis lung cancer cell line to evaluate the therapeutic effect of PD-1 on mice with varying gut microbiota. RESULTS: The results demonstrated a significant association between elevated gut microbiota diversity and response to treatment with ICIs, p < 0.05. Faecalibacterium was markedly increased in the gut microbiota of responders (R), accompanied by increased short-chain fatty acid (SCFA) levels, especially butanoic acid, acetic acid and hexanoic acid, p < 0.05. Additionally, FMT from R and nonresponders (NR) could promote an anticancer effect and reduce the expression of Ki-67 cells in tumors in mice, p < 0.05. Moreover, R and NR FMT did not alter PD-L1 expression in the tumor tissues of mice, p > 0.05. The diversity of gut microbiota consistently correlated with an optimistic prognosis in NSCLC patients with immunotherapy, which could be functionally mediated by SCFAs. CONCLUSION: The findings of the present study indicated that the diversity of gut microbiota and SCFAs is related to the efficacy of immunotherapy. FMT can effectively delay tumor progression, and enhance the effect of immunotherapy, thus providing evidence for improving the efficacy of immunotherapy in NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas , Microbioma Gastrointestinal , Imunoterapia , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/terapia , Animais , Camundongos , Humanos , Neoplasias Pulmonares/terapia , Imunoterapia/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
BACKGROUND: Cancer immunotherapy is receiving worldwide attention for its induction of an anti-tumor response. However, it has had limited efficacy in some patients who acquired resistance. The dynamic and sophisticated complexity of the tumor microenvironment (TME) is the leading contributor to this clinical dilemma. Through recapitulating the physiological features of the TME, 3D bioprinting is a promising research tool for cancer immunotherapy, which preserves in vivo malignant aggressiveness, heterogeneity, and the cell-cell/matrix interactions. It has been reported that application of 3D bioprinting holds potential to address the challenges of immunotherapy resistance and facilitate personalized medication. CONCLUSIONS AND PERSPECTIVES: In this review, we briefly summarize the contributions of cellular and noncellular components of the TME in the development of immunotherapy resistance, and introduce recent advances in 3D bioprinted tumor models that served as platforms to study the interactions between tumor cells and the TME. By constructing multicellular 3D bioprinted tumor models, cellular and noncellular crosstalk is reproduced between tumor cells, immune cells, fibroblasts, adipocytes, and the extracellular matrix (ECM) within the TME. In the future, by quickly preparing 3D bioprinted tumor models with patient-derived components, information on tumor immunotherapy resistance can be obtained timely for clinical reference. The combined application with tumoroid or other 3D culture technologies will also help to better simulate the complexity and dynamics of tumor microenvironment in vitro. We aim to provide new perspectives for overcoming cancer immunotherapy resistance and inspire multidisciplinary research to improve the clinical application of 3D bioprinting technology.
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Bioimpressão , Imunoterapia , Impressão Tridimensional , Microambiente Tumoral , Microambiente Tumoral/imunologia , Humanos , Bioimpressão/métodos , Imunoterapia/métodos , Animais , Neoplasias/imunologia , Neoplasias/terapia , Resistencia a Medicamentos Antineoplásicos/imunologia , Modelos Biológicos , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismoRESUMO
Endocrine therapy (ET) is a well-validated strategy for estrogen receptor α positive (ERα + ) breast cancer therapy. Despite the clinical success of current standard of care (SoC), endocrine-resistance inevitably emerges and remains a significant medical challenge. Herein, we describe the structural optimization and evaluation of a new series of selective estrogen receptor covalent antagonists (SERCAs) based on benzothiophene scaffold. Among them, compounds 15b and 39d were identified as two highly potent covalent antagonists, which exhibits superior antiproliferation activity than positive controls against MCF-7 cells and shows high selectivity over ERα negative (ERα-) cells. More importantly, their mode of covalent engagement at Cys530 residue was accurately illustrated by a cocrystal structure of 15b-bound ERαY537S (PDB ID: 7WNV) and intact mass spectrometry, respectively. Further in vivo studies demonstrated potent antitumor activity in MCF-7 xenograft mouse model and an improved safety profile. Collectively, these compounds could be promising candidates for future development of the next generation SERCAs for endocrine-resistant ERα + breast cancer.
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Neoplasias da Mama , Antagonistas do Receptor de Estrogênio , Humanos , Camundongos , Animais , Feminino , Receptor alfa de Estrogênio , Receptores de Estrogênio , Cristalografia por Raios X , Neoplasias da Mama/tratamento farmacológico , Células MCF-7 , Antagonistas de EstrogêniosRESUMO
Recurrent miscarriage (RM) is a distressing pregnancy complication. While the etiology of RM remains unclear, growing evidence has indicated the relevance of trophoblast impairment to the pathogenesis of RM. PR-SET7 is the sole enzyme catalyzing monomethylation of H4K20 (H4K20me1) and has been implicated in many pathophysiological processes. However, how PR-SET7 functions in trophoblasts and its relevance to RM remain unknown. Here, we found that trophoblast-specific loss of Pr-set7 in mice led to defective trophoblasts, resulting in early embryonic loss. Mechanistic analysis revealed that PR-SET7 deficiency in trophoblasts derepressed endogenous retroviruses (ERVs), leading to double-stranded RNA stress and subsequent viral mimicry, which drove overwhelming interferon response and necroptosis. Further examination discovered that H4K20me1 and H4K20me3 mediated the inhibition of cell-intrinsic expression of ERVs. Importantly, dysregulation of PR-SET7 expression and the corresponding aberrant epigenetic modifications were observed in the placentas of RM. Collectively, our results demonstrate that PR-SET7 acts as an epigenetic transcriptional modulator essential for repressing ERVs in trophoblasts, ensuring normal pregnancy and fetal survival, which sheds new light on potential epigenetic causes contributing to RM.
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Aborto Habitual , Retrovirus Endógenos , Feminino , Gravidez , Humanos , Animais , Camundongos , Trofoblastos , Necroptose , PlacentaRESUMO
Colorectal cancer (CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies, which can be summarized into two aspects: (1) The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism, drug transport, drug target, and the activation of signaling pathways; and (2) the suppressive features of the tumor microenvironment (TME). To combat the issue of therapeutic resistance, effective strategies are warranted with a focus on the restoration of CRC cells' sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions. To date, nanotechnology seems promising with scope for improvement of drug mobility, treatment efficacy, and reduction of systemic toxicity. The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity, as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence, metastasis, and reversion of therapy resistance. The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy, radiotherapy, immunotherapy, and targeted therapy, as well as the process of metastasis. We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone. In summary, nanomedicine is an emerging technology with potential for CRC treatment; hence, efforts should be devoted to targeting cancer cells for the restoration of therapeutic sensitivity as well as reprogramming the TME. It is believed that the combined strategy will be beneficial to achieve synergistic outcomes contributing to control and management of CRC in the future.
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Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Humanos , Nanotecnologia , Sistemas de Liberação de Medicamentos , Imunoterapia , Neoplasias Colorretais/tratamento farmacológico , Microambiente TumoralRESUMO
Cancertestis antigen (CTA) is a wellaccepted optimal target library for cancer diagnosis and treatment. Most CTAs are located on the X chromosome and aggregate into large gene families, such as the melanoma antigen, synovial sarcoma X and G antigen families. Members of the CTA subfamily are usually coexpressed in tumor tissues and share similar structural characteristics and biological functions. As cancer vaccines are recommended to induce specific antitumor responses, CTAs, particularly CTA subfamilies, are widely used in the design of cancer vaccines. To date, DNA, mRNA and peptide vaccines have been commonly used to generate tumorspecific CTAs in vivo and induce anticancer effects. Despite promising results in preclinical studies, the antitumor efficacy of CTAbased vaccines is limited in clinical trials, which may be partially attributed to weak immunogenicity, low efficacy of antigen delivery and presentation processes, as well as a suppressive immune microenvironment. Recently, the development of nanomaterials has enhanced the cancer vaccination cascade, improved the antitumor performance and reduced offtarget effects. The present study provided an indepth review of the structural characteristics and biofunctions of the CTA subfamilies, summarised the design and utilisation of CTAbased vaccine platforms and provided recommendations for developing nanomaterialderived CTAtargeted vaccines.
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Vacinas Anticâncer , Melanoma , Humanos , Masculino , Antígenos de Neoplasias/genética , Imunidade , Melanoma/genética , Testículo , Microambiente TumoralRESUMO
PURPOSE: Cancer testis antigens (CTAs) are optimal tumor diagnostic markers and involved in carcinogenesis. However, colorectal cancer (CRC) related CTAs are less reported with impressive diagnostic capability or relevance with tumor metabolism rewiring. Herein, we demonstrated CRC-related CTA, Protamine 1 (PRM1), as a promising diagnostic marker and involved in regulation of cellular growth under nutrient deficiency. METHODS: Transcriptomics of five paired CRC tissues was used to screen CRC-related CTAs. Capability of PRM1 to distinguish CRC was studied by detection of clinical samples through enzyme linked immunosorbent assay (ELISA). Cellular functions were investigated in CRC cell lines through in vivo and in vitro assays. RESULTS: By RNA-seq and detection in 824 clinical samples from two centers, PRM1 expression were upregulated in CRC tissues and patients` serum. Serum PRM1 showed impressive accuracy to diagnose CRC from healthy controls and benign gastrointestinal disease patients, particularly more sensitive for early-staged CRC. Furthermore, we reported that when cells were cultured in serum-reduced medium, PRM1 secretion was upregulated, and secreted PRM1 promoted CRC growth in culture and in mice. Additionally, G1/S phase transition of CRC cells was facilitated by PRM1 protein supplementation and overexpression via activation of PI3K/AKT/mTOR pathway in serum deficient medium. CONCLUSIONS: In general, our research presented PRM1 as a specific CRC antigen and illustrated the importance of PRM1 in CRC metabolism rewiring. The new vulnerability of CRC cells was also provided with the potential to be targeted in future. Diagnostic value and grow factor-like biofunction of PRM1 A represents the secretion process of PRM1 regulated by nutrient deficiency. B represents activation of PI3K/AKT/mTOR pathway of secreted PRM1.
Assuntos
Proliferação de Células , Neoplasias Colorretais , Protaminas , Estresse Fisiológico , Animais , Humanos , Masculino , Camundongos , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Nutrientes/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Protaminas/imunologia , Protaminas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fase S , Estresse Fisiológico/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI),is the currently recommended first-line therapy for advanced EGFR-mutant lung cancer, and understanding the mechanism of resistance is the key to formulating therapeutic strategies for EGFR-TKIs. In this study, we evaluate the expression patterns and potential biological functions of the pseudogene DUXAP10 in gefitinib resistance. We find that pseudogene DUXAP10 expression is significantly upregulated in NSCLC gefitinib-resistant cells and tissues. Gain and loss of function assays reveal that knockdown of DUXAP10 by siRNA reverses gefitinib resistance both in vitro and in vivo. Furthermore, DUXAP10 interacts with the histone methyltransferase enhancer of zeste homolog 2 (EZH2) to repress the expression of 2',5'-oligoadenylate synthetase (OAS2). Overall, our study highlights the pivotal role of DUXAP10 in gefitinib resistance, and the DUXAP10/EZH2/OAS2 axis might be a promising therapeutic target to overcome acquired gefitinib resistance in NSCLC.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Gefitinibe , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Pseudogenes , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Ligases/genética , Ligases/farmacologia , Ligases/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pseudogenes/genéticaRESUMO
The placenta, forming the maternal-fetal interface, is essential for the survival and development of the fetus. It has been shown that the basic helix-loop-helix (bHLH) transcription factor Hand1 plays an important role in trophoblast giant cells (TGCs) differentiation during placental development in mice. However, the underlying molecular mechanism remains elusive. We hereby report that Adgrg1 (GPR56), a G protein coupled receptor, was a new transcriptional target of Hand1. Hand1 activated the expression of Adgrg1 by binding to its promoter region during TGCs differentiation. Double in situ hybridization revealed co-expression of Hand1 and Adgrg1 in Prl2c2+ TGCs located in the junctional zone of the placenta. Knockdown of Adgrg1 not only led to increased Prl2c2 expression, but also the improvement of cell migration and invasion during TGC differentiation. Moreover, the ligand of Adgrg1, Tgm2, was expressed in Prl2c2+ TGCs located in the placental junctional zone and Tgm2 Knockdown increased cell migration and invasion, suggesting Tgm2 is a potential ligand involved in the functions of Adgrg1 during TGC differentiation in the manners of autocrine. Collectively, these results demonstrate that Adgrg1 is a new transcriptional target of Hand1, affecting Prl2c2 expression as well as cell migration and invasion during TGCs differentiation. As a transmembrane receptor, Adgrg1 perhaps could act as a potential therapeutic target for placental-associated diseases caused by abnormal trophoblast migration and invasion, providing new insights for the preventions and therapies of placenta-related diseases.
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Placenta , Trofoblastos , Feminino , Camundongos , Gravidez , Animais , Trofoblastos/metabolismo , Placenta/metabolismo , Ligantes , Diferenciação Celular , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Background: 18F-FDG PET/CT is widely used in the prognosis evaluation of tumor patients. The radiomics features can provide additional information for clinical prognostic assessment. Purpose: Purpose is to explore the prognostic value of radiomics features from dual-time 18F-FDG PET/CT images for locally advanced pancreatic cancer (LAPC) patients treated with stereotactic body radiation therapy (SBRT). Materials and Methods: This retrospective study included 70 LAPC patients who received early and delayed 18F-FDG PET/CT scans before SBRT treatment. A total of 1188 quantitative imaging features were extracted from dual-time PET/CT images. To avoid overfitting, the univariate analysis and elastic net were used to obtain a sparse set of image features that were applied to develop a radiomics score (Rad-score). Then, the Harrell consistency index (C-index) was used to evaluate the prognosis model. Results: The Rad-score from dual-time images contains six features, including intensity histogram, morphological, and texture features. In the validation cohort, the univariate analysis showed that the Rad-score was the independent prognostic factor (p < 0.001, hazard ratio [HR]: 3.2). And in the multivariate analysis, the Rad-score was the only prognostic factor (p < 0.01, HR: 4.1) that was significantly associated with the overall survival (OS) of patients. In addition, according to cross-validation, the C-index of the prognosis model based on the Rad-score from dual-time images is better than the early and delayed images (0.720 vs. 0.683 vs. 0.583). Conclusion: The Rad-score based on dual-time 18F-FDG PET/CT images is a promising noninvasive method with better prognostic value.
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Concomitant inhibition of estrogen receptor alpha (ERα) and histone deacetylase (HDAC) signaling has been proven effective in endocrine-resistant ER+ breast cancers. Herein, a series of tetrahydroisoquinoline (THIQ)-hydroxamate conjugates were rationally designed and synthesized as dual SERDs/HDAC inhibitors by incorporating the hydroxamate, a known HDAC pharmacophore, into a privileged THIQ scaffold of selective ERα degraders (SERDs). Some of these THIQ-hydroxamate conjugates displayed remarkable HDAC6 inhibition and improved antiproliferative activity against MCF-7 cells. Particularly, the most potent HDAC inhibitor 19k also exhibits potent ERα binding affinity, good ERα degradation efficacy and the best antiproliferative activity. Besides, 19k displayed superior antitumor efficacy than the drug combination (Fulvestrant + SAHA) through promoting ERα degradation and histone acetylation in an MCF-7 xenograft model, without causing observable toxicity. Collectively, this study validates the therapeutic potential of a dual-acting compound with potent ERα degradation efficacy and HDAC6 inhibition in breast cancer.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenvolvimento de Medicamentos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Feminino , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Células Tumorais CultivadasRESUMO
5-Fluorouracil (5-Fu) is a widely applied anti-cancer agent against colorectal cancer (CRC), yet a number of CRC patients have developed resistance to 5-Fu-based chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as an oncogene that promotes diverse cancer progresses. In addition, long noncoding RNAs (lncRNAs) are essential regulators of cancers. Here we report that EGFR and lncRNA-FGD5-AS1 promoted 5-Fu resistance of CRC. By establishing the 5-Fu-resistant CRC cell line, we detected that EGFR, FGD5-AS1, and glucose metabolism were significantly elevated in 5-Fu-resistant CRC cells. A microRNA-microarray analysis revealed that miR-330-3p functions as a downstream effector of FGD5-AS1. FGD5-AS1 directly sponged miR-330-3p to form a competing endogenous RNA (ceRNA) network, leading to inhibition of miR-330-3p expression. Furthermore, bioinformatics analysis revealed that Hexokinase 2 (HK2) was a potential target of miR-330-3p, which was validated by luciferase assay. Rescue experiments demonstrated that FGD5-AS1 promotes glycolysis through modulating the miR-330-3p-HK2 axis, leading to 5-Fu resistance of CRC cancer cells. Finally, in vitro and in vivo xenograft experiments consistently demonstrated that inhibition of EGFR by the specific inhibitor erlotinib effectively enhanced the anti-tumor toxicity of 5-Fu by targeting the EGFR-FGD5-AS1-miR-330-3p-HK2 pathway. In summary, this study demonstrates new mechanisms of the EGFR-modulated 5-Fu resistance through modulating the noncoding RNA network, contributing to development of new approaches against chemoresistant CRC.
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BACKGROUND: To explore the diagnostic value of three different measurement approaches in differentiating T1a-T1b from T2 gastric cancer (GC) lesions. METHODS: A total of 95 consecutive patients with T1a-T2 stage of GC who performed preoperative MRI were retrospectively enrolled between January 2017 and November 2020. The parameters MRI T stage (subjective evaluation), thickness, maximum area and volume of the lesions were evaluated by two radiologists. Specific indicators including AUC, optimal cutoff, sensitivity, specificity, accuracy, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV) and negative predictive value (NPV) of MRI T stage, thickness, maximum area and volume for differentiating T1a-T1b from T2 stage lesions were calculated. The ROC curves were compared by the Delong test. Decision curve analysis (DCA) was used to evaluate the clinical benefit. RESULTS: The ROC curves for thickness (AUC = 0.926), maximum area (AUC = 0.902) and volume (AUC = 0.897) were all significantly better than those of the MRI T stage (AUC = 0.807) in differentiating T1a-T1b from T2 lesions, with p values of 0.004, 0.034 and 0.041, respectively. The values corresponding to the thickness (including AUC, sensitivity, specificity, accuracy, PPV, NPV, PLR and NLR) were all higher than those corresponding to the MRI T stage, maximum area and volume. The DCA curves indicated that the parameter thickness could provide the highest clinical benefit if the threshold probability was above 35%. CONCLUSIONS: Thickness may provide an efficient approach to rapidly distinguish T1a-T1b from T2 stage GC lesions.
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Imageamento por Ressonância Magnética/métodos , Estadiamento de Neoplasias/métodos , Neoplasias Gástricas/diagnóstico por imagem , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Curva ROC , Estudos Retrospectivos , Neoplasias Gástricas/patologiaRESUMO
Estrogen receptor α emerged as a well validated therapeutic target of breast cancer for decades. However, approximately 50% of patients who initially responding to standard-of-care (SoC), such as undergo therapy of Tamoxifen, generally inevitably progress to an endocrine-resistance ER+ phenotype. Recently, selective estrogen receptor covalent antagonists (SERCAs) targeted to ERα have been demonstrated as a therapeutic alternative. In the present study, series of novel 6-OH-benzothiophene (BT) derivatives targeting ERα and deriving from Raloxifene were designed, synthesized, and biologically evaluated as covalent antagonists. Driven by the antiproliferative efficacy in ER+ breast cancer cells, our chemical optimization finally led to compound 19d that with potent antagonistic activity in ER+ tumor cells while without agonistic activity in endometrial cells. Moreover, the docking simulation was carried out to elucidate the binding mode, revealing 19d as an antagonist and covalently binding to the cysteine residue at the 530 position of ER helix H11.
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Desenho de Fármacos , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Tiofenos/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/química , Receptor alfa de Estrogênio/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
The objective of this study was to investigate the effects of dietary administration of l-arginine (Arg) or N-carbamylglutamate (NCG) on hepatic energy status and mitochondrial functions in suckling Hu lambs with intrauterine growth retardation (IUGR). Forty-eight newborn Hu lambs of 7 d old were allocated into 4 treatment groups of 12 lambs each, in triplicate with 4 lambs per replicate (2 males and 2 females) as follows: CON (lambs of normal birth weight, 4.25 ± 0.14 kg), IUGR (3.01 ± 0.12 kg), IUGR + 1% Arg (2.99 ± 0.13 kg), or IUGR + 0.1% NCG (3.03 ± 0.11 kg). The experiment lasted for 21 d, until d 28 after birth, and all lambs were fed milk replacer as a basal diet. Compared with IUGR lambs, NCG or Arg administration increased (P < 0.05) the adenosine triphosphate (ATP) level and the activities of complexes I/III/IV, isocitrate dehydrogenase and citrate synthase in the liver. Compared with CON lambs, the relative mRNA levels of adenosine monophosphate-activated protein kinase α1 (AMPKα1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) and transcription factor A (TFAM) were increased (P < 0.05) in the liver of IUGR lambs, but were decreased (P < 0.05) in the liver of NCG- or Arg-treated lambs compared with those in the IUGR lambs. Compared with IUGR lambs, NCG or Arg administration decreased (P < 0.05) the total AMPKα (tAMPKα)-to-phosphorylated AMPKα (pAMPKα) ratio and the protein expression of PGC1α and TFAM. The results suggested that dietary Arg or NCG supplements improved hepatic energy status and mitochondrial function and inhibited the AMPK-PGC1α-TFAM pathway in IUGR suckling lambs.
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The mammalian placenta consists of a set of cells to ensure normal placental functions throughout gestation. Dysfunctional placentae are considered as the origin of a series of pregnancy complications. Therefore, it is urgent for detailed information about the molecular recipes of the cell types within the normal placenta. In the past years, gene expression analysis via single-cell RNA-seq (scRNA-seq) offers opportunities to identify new cell types in a variety of organs and tissues. In this study, scRNA-seq was used to explore the cell heterogeneity within the E10.5 mouse placenta and unravel their discrepancies in cell composition and communications. We identified sixteen cell clusters, including some cell clusters that originated from the maternal tissue. Moreover, we traced the developmental trajectories of trophoblasts and Hofbauer-like cells. Further analysis revealed cell connections between the endothelial cells and pericytes, syncytiotrophoblasts, as well as decidual cells. Besides, we highlighted several signaling pathways, such as the EGF, FGF, canonical, and non-canonical WNT signaling pathways, which mediated the potential crosstalk between different cell types within placenta. Our research provides an in-depth understanding of placental development, cellular composition, and communications at the maternal-fetal interface.
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Células Endoteliais/citologia , Placenta/metabolismo , Complicações na Gravidez/metabolismo , RNA/metabolismo , Animais , Feminino , Expressão Gênica/fisiologia , Perfilação da Expressão Gênica/métodos , Camundongos , Gravidez , Análise de Célula Única/métodos , Trofoblastos/metabolismoRESUMO
Endocrine therapy (ET) has benefited patients with estrogen receptor alpha (ERα) positive breast cancer for decades. Selective estrogen receptor modulator (SERM) such as Tamoxifen represents the clinical standard of care (SoC). Despite the therapeutic importance of current SoC agents, 30-50% of prolonged treatment patients inevitably generated resistant tumor cells, usually eventually suffered tumor relapse and developed into metastatic breast cancer (MBC), which was the leading cause of female cancer-related mortality. Among these, most resistant tumors remained dependent on ERα signaling, which reignited the need for the next generation of ERα related agents. We hypothesized that selective estrogen receptor covalent antagonists targeting ERα would provide a therapeutic alternative. In the current work, series of novel benzothiophene hybrids bearing electrophile moieties were synthesized and biologically evaluated. The representative analogue 15c exhibited potent anti-proliferative effect in MCF-7 cell lines in vitro, and further mechanism studies confirmed the necessity of covalent bonding. More importantly, 15c could attenuate the expression of TFF-1, GREB-1 and downregulate the levels of cellular ERα protein.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenho de Fármacos , Antagonistas do Receptor de Estrogênio/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Tiofenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas do Receptor de Estrogênio/síntese química , Antagonistas do Receptor de Estrogênio/química , Feminino , Humanos , Células MCF-7 , Estrutura Molecular , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Células Tumorais CultivadasRESUMO
OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) and autoimmune pancreatitis (AIP) are diseases with a highly analogous visual presentation that are difficult to distinguish by imaging. The purpose of this research was to create a radiomics-based prediction model using dual-time PET/CT imaging for the noninvasive classification of PDAC and AIP lesions. METHODS: This retrospective study was performed on 112 patients (48 patients with AIP and 64 patients with PDAC). All cases were confirmed by imaging and clinical follow-up, and/or pathology. A total of 502 radiomics features were extracted from the dual-time PET/CT images to develop a radiomics decision model. An additional 12 maximum intensity projection (MIP) features were also calculated to further improve the radiomics model. The optimal radiomics feature set was selected by support vector machine recursive feature elimination (SVM-RFE), and the final classifier was built using a linear SVM. The performance of the proposed dual-time model was evaluated using nested cross-validation for accuracy, sensitivity, specificity, and area under the curve (AUC). RESULTS: The final prediction model was developed from a combination of the SVM-RFE and linear SVM with the required quantitative features. The multimodal and multidimensional features performed well for classification (average AUC: 0.9668, accuracy: 89.91%, sensitivity: 85.31%, specificity: 96.04%). CONCLUSIONS: The radiomics model based on 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET/CT dual-time images provided promising performance for discriminating between patients with benign AIP and malignant PDAC lesions, which shows its potential for use as a diagnostic tool for clinical decision-making. KEY POINTS: ⢠The clinical symptoms and imaging visual presentations of PDAC and AIP are highly similar, and accurate differentiation of PDAC and AIP lesions is difficult. ⢠Radiomics features provided a potential noninvasive method for differentiation of AIP from PDAC. ⢠The diagnostic performance of the proposed radiomics model indicates its potential to assist doctors in making treatment decisions.