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1.
Lancet Oncol ; 25(2): 184-197, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38211606

RESUMO

BACKGROUND: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , China , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
2.
J Transl Med ; 22(1): 560, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867219

RESUMO

BACKGROUND: Cardiac fibrosis after myocardial infarction (MI) has been considered an important part of cardiac pathological remodeling. Immune cells, especially macrophages, are thought to be involved in the process of fibrosis and constitute a niche with fibroblasts to promote fibrosis. However, the diversity and variability of fibroblasts and macrophages make it difficult to accurately depict interconnections. METHODS: We collected and reanalyzed scRNA-seq and snRNA-seq datasets from 12 different studies. Differentiation trajectories of these subpopulations after MI injury were analyzed by using scVelo, PAGA and Slingshot. We used CellphoneDB and NicheNet to infer fibroblast-macrophage interactions. Tissue immunofluorescence staining and in vitro experiments were used to validate our findings. RESULTS: We discovered two subsets of ECM-producing fibroblasts, reparative cardiac fibroblasts (RCFs) and matrifibrocytes, which appeared at different times after MI and exhibited different transcriptional profiles. We also observed that CTHRC1+ fibroblasts represent an activated fibroblast in chronic disease states. We identified a macrophage subset expressing the genes signature of SAMs conserved in both human and mouse hearts. Meanwhile, the SPP1hi macrophages were predominantly found in the early stages after MI, and cell communication analysis indicated that SPP1hi macrophage-RCFs interactions are mainly involved in collagen deposition and scar formation. CONCLUSIONS: Overall, this study comprehensively analyzed the dynamics of fibroblast and macrophage subsets after MI and identified specific subsets of fibroblasts and macrophages involved in scar formation and collagen deposition.


Assuntos
Fibroblastos , Macrófagos , Infarto do Miocárdio , Análise de Célula Única , Transcriptoma , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Macrófagos/metabolismo , Animais , Transcriptoma/genética , Humanos , Comunicação Celular , Camundongos , Diferenciação Celular/genética , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miocárdio/metabolismo , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica
3.
Environ Sci Technol ; 58(1): 751-759, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38113379

RESUMO

Aquatic environments are complicated systems that contain different types of nanoparticles (NPs). Nevertheless, recent studies of NP toxicity, and especially those that have focused on bioaccumulation have mostly investigated only a single type of NPs. Assessments of the environmental risks of NPs that do not consider co-exposure regimes may lead to inaccurate conclusions and ineffective environmental regulation. Thus, the present study examined the effects of differently sized silica NPs (SiO2 NPs) on the uptake of iron oxide NPs (Fe2O3 NPs) by the zooplankton Daphnia magna. Both SiO2 NPs and Fe2O3 NPs were well dispersed in the experimental medium without significant heteroaggregation. Although all three sizes of SiO2 NPs inhibited the uptake of Fe2O3 NPs, the underlying mechanisms differed. SiO2 NPs smaller than the average mesh size (∼200 nm) of the filtering apparatus of D. magna reduced the accumulation of Fe2O3 NPs through uptake competition, whereas larger SiO2 NPs inhibited the uptake of Fe2O3 NPs mainly by reducing the water filtration rate of the daphnids. Overall, in evaluations of the risks of NPs in the natural environment, the different mechanisms underlying the effects of NPs of different sizes on the uptake of dissimilar NPs should be considered.


Assuntos
Nanopartículas , Poluentes Químicos da Água , Animais , Daphnia magna , Daphnia , Dióxido de Silício/farmacologia , Nanopartículas/toxicidade , Nanopartículas Magnéticas de Óxido de Ferro , Poluentes Químicos da Água/toxicidade
4.
Acta Pharmacol Sin ; 45(6): 1175-1188, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38459256

RESUMO

Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with oxidative stress, inflammation and apoptosis in the heart. MACRO domain containing 1 (Macrod1) is an ADP-ribosylhydrolase 1 that is highly enriched in mitochondria, participating in the pathogenesis of cardiovascular diseases. In this study, we investigated the role of Macrod1 in DCM. A mice model was established by feeding a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). We showed that Macrod1 expression levels were significantly downregulated in cardiac tissue of DCM mice. Reduced expression of Macrod1 was also observed in neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA, 400 µM) in vitro. Knockout of Macrod1 in DCM mice not only worsened glycemic control, but also aggravated cardiac remodeling, mitochondrial dysfunction, NAD+ consumption and oxidative stress, whereas cardiac-specific overexpression of Macrod1 partially reversed these pathological processes. In PA-treated NRCMs, overexpression of Macrod1 significantly inhibited PARP1 expression and restored NAD+ levels, activating SIRT3 to resist oxidative stress. Supplementation with the NAD+ precursor Niacin (50 µM) alleviated oxidative stress in PA-stimulated cardiomyocytes. We revealed that Macrod1 reduced NAD+ consumption by inhibiting PARP1 expression, thereby activating SIRT3 and anti-oxidative stress signaling. This study identifies Macrod1 as a novel target for DCM treatment. Targeting the PARP1-NAD+-SIRT3 axis may open a novel avenue to development of new intervention strategies in DCM. Schematic illustration of macrod1 ameliorating diabetic cardiomyopathy oxidative stress via PARP1-NAD+-SIRT3 axis.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , NAD , Estresse Oxidativo , Poli(ADP-Ribose) Polimerase-1 , Sirtuína 3 , Animais , Masculino , Camundongos , Ratos , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Dieta Hiperlipídica , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , NAD/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Sirtuína 3/genética , Estreptozocina
5.
J Chem Phys ; 160(13)2024 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-38557836

RESUMO

VO2 is renowned for its electric transition from an insulating monoclinic (M1) phase, characterized by V-V dimerized structures, to a metallic rutile (R) phase above 340 K. This transition is accompanied by a magnetic change: the M1 phase exhibits a non-magnetic spin-singlet state, while the R phase exhibits a state with local magnetic moments. Simultaneous simulation of the structural, electric, and magnetic properties of this compound is of fundamental importance, but the M1 phase alone has posed a significant challenge to the density functional theory (DFT). In this study, we show none of the commonly used DFT functionals, including those combined with on-site Hubbard U to treat 3d electrons better, can accurately predict the V-V dimer length. The spin-restricted method tends to overestimate the strength of the V-V bonds, resulting in a small V-V bond length. Conversely, the spin-symmetry-breaking method exhibits the opposite trends. Each of these two bond-calculation methods underscores one of the two contentious mechanisms, i.e., Peierls lattice distortion or Mott localization due to electron-electron repulsion, involved in the metal-insulator transition in VO2. To elucidate the challenges encountered in DFT, we also employ an effective Hamiltonian that integrates one-dimensional magnetic sites, thereby revealing the inherent difficulties linked with the DFT computations.

6.
Hepatobiliary Pancreat Dis Int ; 23(3): 272-287, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37407412

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) has a poor long-term prognosis. The competition of circular RNAs (circRNAs) with endogenous RNA is a novel tool for predicting HCC prognosis. Based on the alterations of circRNA regulatory networks, the analysis of gene modules related to HCC is feasible. METHODS: Multiple expression datasets and RNA element targeting prediction tools were used to construct a circRNA-microRNA-mRNA network in HCC. Gene function, pathway, and protein interaction analyses were performed for the differentially expressed genes (DEGs) in this regulatory network. In the protein-protein interaction network, hub genes were identified and subjected to regression analysis, producing an optimized four-gene signature for prognostic risk stratification in HCC patients. Anti-HCC drugs were excavated by assessing the DEGs between the low- and high-risk groups. A circRNA-microRNA-hub gene subnetwork was constructed, in which three hallmark genes, KIF4A, CCNA2, and PBK, were subjected to functional enrichment analysis. RESULTS: A four-gene signature (KIF4A, CCNA2, PBK, and ZWINT) that effectively estimated the overall survival and aided in prognostic risk assessment in the The Cancer Genome Atlas (TCGA) cohort and International Cancer Genome Consortium (ICGC) cohort was developed. CDK inhibitors, PI3K inhibitors, HDAC inhibitors, and EGFR inhibitors were predicted as four potential mechanisms of drug action (MOA) in high-risk HCC patients. Subsequent analysis has revealed that PBK, CCNA2, and KIF4A play a crucial role in regulating the tumor microenvironment by promoting immune cell invasion, regulating microsatellite instability (MSI), and exerting an impact on HCC progression. CONCLUSIONS: The present study highlights the role of the circRNA-related regulatory network, identifies a four-gene prognostic signature and biomarkers, and further identifies novel therapy for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , RNA Circular/genética , Prognóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , RNA Endógeno Competitivo , Fosfatidilinositol 3-Quinases , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , MicroRNAs/genética , Microambiente Tumoral , Cinesinas
7.
Phys Chem Chem Phys ; 25(10): 7445-7452, 2023 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-36848102

RESUMO

Cu-chalcogenides are a large group of multifunctional compounds traditionally used in photovoltaics and optoelectronics. Their bandgap sizes usually decrease with the element masses, e.g., 2.68, 1.68, and 1.04 eV for CuAlSe2, CuGaSe2, and CuInSe2, respectively. Cu-Tl-X (X = S/Se/Te) with even heavier thallium (Tl) has received recent attention in topological insulators and high-performance thermoelectric converters. While the novel applications may be related to Tl relativistic effects, first-principles investigations are scarce for these complex compounds. Here, we reveal the relativistic effects in Cu-Tl-X using a tailored density-functional-theory approach. Three relativistic terms of mass-velocity, Darwin, and spin-orbit-coupling play distinct roles. In diamond-like CuTlX2, the mass-velocity correction reduces the conduction band position and contributes to minimizing the bandgaps. The relativistic bandgap of CuTlS2 of 0.11 eV is substantially smaller than 1.7 eV without considering the relativistic effects. In CuTlTe2, the spin-orbit-coupling splits the valence bands, resulting in an exotic band inversion. CuTlSe2 lies on the boundary of normal and inverted band topologies. Interestingly, the relativistic core contraction is so strong that it may favor non-centrosymmetric defective structures with stereoactive lone-pair electrons. The bandgap of the defective structure is much larger, leaving the system little chance to develop an inverted band topology. Our work provides deep insights into understanding the relativistic band topologies of the complex Cu-Tl-X compounds.

8.
Exp Cell Res ; 418(2): 113266, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35752345

RESUMO

Cancer-associated fibroblasts secreted exosomes (CAFs-exo) are important for tumor carcinogenesis and chemoresistance, but its underlying mechanism in colorectal cancer (CRC) has not yet been clarified. In this study, we investigated the regulatory mechanism of CAFs-exo cricN4BP2L2 on the proliferation, apoptosis, stemness and chemoresistance of LoVo cells. We found that CAFs-exo promoted the oxaliplatin resistance and stemness of LoVo cells, while inhibited the LoVo cell apoptosis. Moreover, knockdown of cricN4BP2L2 in CAFs-exo inhibited the oxaliplatin resistance and stemness characteristics of LoVo cells. Mechanistically, cricN4BP2L2 regulated PI3K/AKT/mTOR axis by binding to EIF4A3. Rescue experiments proved that CAFs-derived exosomal cricN4BP2L2 promoted CRC cells stemness and oxaliplatin resistance by upregulating EIF4A3. Moreover, in vivo experiments showed that depletion of cricN4BP2L2 suppressed CRC tumorigenesis growth. In conclusion, CAFs-exo cricN4BP2L2 promoted the CRC cells stemness and oxaliplatin resistance through EIF4A3/PI3K/AKT/mTOR pathway.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Exossomos , MicroRNAs , Fibroblastos Associados a Câncer/patologia , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , RNA Helicases DEAD-box/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fator de Iniciação 4A em Eucariotos/metabolismo , Exossomos/metabolismo , Humanos , MicroRNAs/metabolismo , Oxaliplatina , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
9.
Part Fibre Toxicol ; 20(1): 38, 2023 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-37807046

RESUMO

Recently, mesoporous nanomaterials with widespread applications have attracted great interest in the field of drug delivery due to their unique structure and good physiochemical properties. As a biomimetic nanomaterial, mesoporous polydopamine (MPDA) possesses both a superior nature and good compatibility, endowing it with good clinical transformation prospects compared with other inorganic mesoporous nanocarriers. However, the subacute toxicity and underlying mechanisms of biomimetic mesoporous polydopamine nanoparticles remain uncertain. Herein, we prepared MPDAs by a soft template method and evaluated their primary physiochemical properties and metabolite toxicity, as well as potential mechanisms. The results demonstrated that MPDA injection at low (3.61 mg/kg) and medium doses (10.87 mg/kg) did not significantly change the body weight, organ index or routine blood parameters. In contrast, high-dose MPDA injection (78.57 mg/kg) is associated with disturbances in the gut microbiota, activation of inflammatory pathways through the abnormal metabolism of bile acids and unsaturated fatty acids, and potential oxidative stress injury. In sum, the MPDA dose applied should be controlled during the treatment. This study first provides a systematic evaluation of metabolite toxicity and related mechanisms for MPDA-based nanoparticles, filling the gap between their research and clinical transformation as a drug delivery nanoplatform.


Assuntos
Biomimética , Nanopartículas , Nanopartículas/toxicidade , Nanopartículas/química , Compostos de Diazônio
10.
BMC Med Educ ; 23(1): 382, 2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37231484

RESUMO

BACKGROUND: The Organization for Economic Cooperation and Development emphasizes the importance of complex problem-solving (CPS) skills in the 21st century. CPS skills have been linked to academic performance, career development, and job competency training. Reflective learning, which includes journal writing, peer reflection, selfreflection, and group discussion, has been explored to improve critical thinking and problem-solving abilities. The development of various thinking modes and abilities, such as algorithmic thinking, creativity, and empathic concern, all affect problem-solving skills. However, there is a lack of an overall theory to relate variables to each other, which means that different theories need to be integrated to focus on how CPS skills can be effectively trained and improved. METHODS: Data from 136 medical students were analyzed using partial least square structural equation modeling (PLSSEM) and fuzzy set qualitative comparative analysis (fsQCA). A hypothesized model examining the associations between the CPS skills and influence factors was constructed. RESULTS: The evaluation of the structural model showed that some variables had significant influences on CPS skills, while others did not. After deleting the insignificant pathways, a structural model was built, which showed that mediating effects of empathic concern and critical thinking were observed, while personal distress only had a direct effect on CPS skills. The results of necessity showed that only cooperativity and creativity are necessary conditions for critical thinking. The fsQCA analysis provided clues for each different pathway to the result, with all consistency values being higher than 0.8, and most coverage values being between 0.240 and 0.839. The fsQCA confirmed the validity of the model and provided configurations that enhanced the CPS skills. CONCLUSIONS: This study provides evidence that reflective learning based on multi-dimensional empathy theory and 21 stcentury skills theory can improve CPS skills in medical students. These results have practical implications for learning and suggest that educators should consider incorporating reflective learning strategies that focus on empathy and 21 stcentury skills to enhance CPS skills in their curricula.


Assuntos
Aprendizagem , Resolução de Problemas , Humanos , Análise de Classes Latentes , Análise dos Mínimos Quadrados , Pensamento
11.
Zhongguo Zhong Yao Za Zhi ; 48(13): 3664-3677, 2023 Jul.
Artigo em Zh | MEDLINE | ID: mdl-37474998

RESUMO

Based on the metabolomics, this paper systematically analyzed the metabolic substance basis of Zuogui Pills and Yougui Pills in syndrome differentiation and treatment of diminished ovarian reserve(DOR), so as to provide a scientific basis for the traditional Chinese medicine(TCM) syndrome differentiation and treatment of DOR. Patients with DOR of kidney-Yin deficiency syndrome were collected from outpatient department of hospitals and treated with Zuogui Pills for 12 weeks. And kidney-Yang deficiency syndrome were treated with Yougui Pills for 12 weeks. Based on the non-targeted metabolomic research techniques, the potential biomarkers of Zuogui Pills and Yougui Pills in the treatment of DOR with kidney-Yin deficiency and kidney-Yang deficiency, respectively, were screened out, and metabolic pathways of biomarkers were analyzed. The pregnancy rate, basic serum hormone levels [basal follicle-stimulating hormone(bFSH), basal-luteinizing hormone(bLH), basal-estradiol(bE_2), and anti-Müllerian hormone(AMH)], TCM syndrome type score, and Kupperman score were recorded and statistically analyzed after treatment. The results showed that 23 patients with DOR of kidney-Yin deficiency syndrome and 25 patients of kidney-Yang deficiency syndrome were collected. Twenty-six differential metabolites, including L-carnitine, acetyl-CoA, coenzyme A, and coenzyme Q_(10)(CoQ10), were mapped to 12 metabolic pathways in patients with kidney-Yin deficiency treated with Zuogui Pills. Twenty-two differential metabolites, such as adipoyl-CoA, L-lysine, lysine arginine, and α-tocopherol, were mapped to 11 metabolic pathways in patients with kidney-Yang deficiency. After treatment, bFSH and bLH of patients with DOR were significantly lower than those before treatment(P<0.05). Although the comparison of bE_2 and AMH had no significant differences, there was a improvement trend. The TCM syndrome type score and Kupperman score of patients with DOR after TCM treatment were significantly lower than those before treatment(P<0.05).


Assuntos
Reserva Ovariana , Deficiência da Energia Yin , Humanos , Deficiência da Energia Yin/tratamento farmacológico , Deficiência da Energia Yang/tratamento farmacológico , Síndrome , Proteinúria , Biomarcadores
12.
Lab Invest ; 102(1): 38-47, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34326457

RESUMO

Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Dysregulation of circular RNAs (circRNAs) appears to be a critical factor in CRC progression. However, mechanistic studies delineating the role of circRNAs in CRC remain limited. In this study, qRT-PCR and western blot assays were used to measure the expression of genes and proteins. Migration, invasion, proliferation, and apoptosis were examined by wound-healing, transwell, CCK-8, colony formation, and flow cytometry assays, respectively. Molecular interactions were validated by a dual-luciferase report system. A xenograft animal model was established to examine in vivo tumor growth and lung metastasis. Our data indicated that circN4BP2L2 expression was increased in CRC tissues and cell lines. Notably, inhibition of circN4BP2L2 effectively inhibited proliferation, migration, and invasion of LoVo cells, and inhibited tumor growth and metastasis in vivo, whereas the forced expression of circN4BP2L2 facilitated the proliferation, migration, and invasion of HT-29 cells. Mechanistic studies revealed that circN4BP2L2 acted as a molecular sponge of miR-340-5p to competitively promote CXCR4 expression. Furthermore, inhibition of miR-340-5p reversed the anti-cancer effects of circN4BP2L2 or CXCR4 silencing. Our data indicated an oncogenic role of circN4BP2L2 in CRC via regulation of the miR-340-5p/CXCR4 axis, which may be a promising biomarker and target for CRC treatment.


Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Circular/genética , Receptores CXCR4/genética , Animais , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Terapêutica com RNAi/métodos , Homologia de Sequência do Ácido Nucleico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Cancer ; 128(9): 1748-1756, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35213037

RESUMO

BACKGROUND: The standard 5 years of endocrine therapy has demonstrated additional benefits compared with short-term (2-3 years) treatment in patients with estrogen receptor (ER)-positive breast cancer; however, data specific to ER-low positive breast cancer (1%-10% by immunohistochemistry) are limited, and it is unclear whether long-term treatment is still necessary for this subgroup. METHODS: The authors used the prospectively maintained Breast Surgery Database of Fudan University Shanghai Cancer Center for this propensity-matched analysis. The primary end point was disease-free survival. Multivariate Cox regression analysis and propensity score-matching methods were used to minimize bias. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistics were 2-sided. RESULTS: From 2012 to 2017, 22,768 consecutive women had pathologically confirmed, early stage breast cancer, and 1013 (4.45%) were identified with ER-low positive disease. Among these, 634 patients met the inclusion criteria and were divided into 3 groups: those who received no endocrine therapy (n = 89), those who received 2 to 3 years of endocrine therapy (n = 185), and those who received approximately 5 years of endocrine therapy (n = 360). At a median follow-up of 65 months, there was no significant difference in disease-free survival between patients who received 2 to 3 years and 5 years of endocrine therapy (HR, 0.82; 95% CI, 0.51-1.33; P = .43). The findings were consistent after multivariate Cox analysis of the propensity score-matched samples (5 vs 2-3 years of treatment: HR, 0.74; 95% CI, 0.41-1.31; P = .30). CONCLUSIONS: Short-term endocrine therapy for 2 to 3 years might be an alternative for patients who have ER-low positive breast cancer instead of the standard 5 years of treatment.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Feminino , Humanos , Imuno-Histoquímica , Receptores de Estrogênio/análise , Coloração e Rotulagem
14.
Biochem Cell Biol ; 100(3): 213-222, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35263194

RESUMO

Breast cancer is the most common malignant tumour in women. Our research on alloimperatorin from Angelica dahurica showed that alloimperatorin inhibited breast cancer cell viability in a concentration- and time-dependent manner; it also showed that apoptosis and ferroptosis inhibitors significantly weakened the antisurvival effect of alloimperatorin. Alloimperatorin clearly induced breast cancer cell apoptosis and increased the activities of caspase-3, caspase-8, caspase-9, and poly (ADP-ribose) polymerase; it also caused significant mitochondrial shrinkage, promoted the accumulation of Fe2+, reactive oxygen species, and malondialdehyde, and significantly reduced mRNA and protein expression levels of SLC7A11 and GPX4, indicating that alloimperatorin induces ferroptosis. In addition, alloimperatorin significantly promoted Kelch-like ECH-associated protein 1 (Keap1) expression; although it did not affect the expression of PGAM5 (mitochondrial serine/threonine protein phosphatase) and apoptosis-inducing factor mitochondria associated 1 (AIFM1), it significantly reduced the phosphorylation level of AIFM1. After downregulating the expression of Keap1, PGAM5, or AIFM1, the inhibitory effect of alloimperatorin on cell viability was significantly weakened, indicating that alloimperatorin regulates the Keap1/PGAM5/AIFM1 pathway to promote oxeiptosis. Alloimperatorin significantly inhibited the invasion of breast cancer cells, while Keap1 siRNA or GPX4 overexpression vectors significantly enhanced cell invasion and effectively reversed the anti-invasive effect of alloimperatorin. Therefore, alloimperatorin induces breast cancer cell apoptosis, ferroptosis, and oxeiptosis, thereby inhibiting cell growth and invasion.


Assuntos
Neoplasias da Mama , Ferroptose , Apoptose , Neoplasias da Mama/patologia , Feminino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Poli(ADP-Ribose) Polimerases/metabolismo
15.
Mol Med ; 28(1): 2, 2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983361

RESUMO

BACKGROUND: Although long noncoding RNA HLA complex group 18 (lncRNA HCG18) has been suggested to regulate cell growth in several tumours, the function of HCG18 in epithelial ovarian cancer (EOC) and its mechanism are still unclear. METHODS: shRNAs were applied to reduce HCG18 and related genes. For overexpression of miRNA, a miRNA mimic was transfected into cells. Quantitative real-time PCR (qRT-PCR) was used to detect levels of HCG18, miR-29a/b, and mRNAs. MTT, colony formation, wound healing and Transwell assays were used to evaluate cell proliferation, migration and invasion, respectively. A luciferase reporter assay was utilized to evaluate NF-κB activity and the binding of miRNAs with HCG18 or TRAF4/5. BALB nude mice injected with cells stably expressing shHCG18 or shNC were used for in vivo modelling. Subcutaneous tumour growth was monitored in nude mice, and immunohistochemistry (IHC) was used to determine expression of the proliferation marker Ki67. RESULTS: Abnormal expression of HCG18 and miR-29a/b was observed in EOC tissues. Knockdown of HCG18 using shRNA inhibited proliferation, migration, EMT and the proinflammatory pathway in EOC cells. miR-29a/b mimics and TRAF4/5 knockdown exhibited effects similar to HCG18 knockdown. Further experiments suggested that HCG18 directly targets miR-29a/b and upregulates TRAF4/5 expression, which are inhibited by targeting miR-29a/b. Moreover, overexpression of TRAF4/5 antagonized the inhibitory effect of HCG18 knockdown, suggesting that they are involved in HCG18-mediated oncogenic effects. Silencing HCG18 reduced tumour size and levels of Ki67 and TRAF4/5 while increasing miR-29a/b levels in vivo. CONCLUSIONS: Taken together, our data revealed an oncogenic signalling pathway mediated by HCG18 in ovarian cell lines, which functions as a ceRNA of miR-29a/b and thus derepresses expression levels of TRAF4/5, facilitating NF-κB pathway-mediated promotion of EOC cell proliferation and migration.


Assuntos
Carcinoma Epitelial do Ovário/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Fator 4 Associado a Receptor de TNF/genética , Fator 5 Associado a Receptor de TNF/genética , Regiões 3' não Traduzidas , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Interferência de RNA , Transdução de Sinais
16.
Breast Cancer Res Treat ; 196(1): 97-109, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36040640

RESUMO

PURPOSE: Salvage mastectomy is traditionally recommended for patients who developed ipsilateral breast tumor recurrence (IBTR) in light of previous breast irradiation. However, it remains controversial whether surgical axillary staging (SAS) is necessary for IBTR patients with negative nodes. This study aimed to evaluate the oncologic safety of omitting SAS for IBTR. METHODS: We retrospectively identified patients who developed invasive IBTR with negative nodes after undergoing breast-conserving surgery (BCS) from 2010 to 2018. Patterns of care in nodal staging were analyzed based on prior axillary staging status. Clinicopathologic characteristics and adjuvant treatment of the initial tumor, as well as the IBTR, were compared between the SAS and no SAS groups. Kaplan-Meier method and Cox regression model were utilized to compare the locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates after IBTR removal between the two groups. RESULTS: A total of 154 IBTR patients were eligible for final analysis. Compared to the no SAS group, SAS group was less likely to undergo ALND (15.1 vs 73.3%, p < 0.001) at initial BCS, had a longer recurrence interval (2.8 vs 2.1 years, p = 0.03), and were more likely to have discordant molecular subtype (35.8 vs 12.9%, p = 0.001) and different quadrant location (37.7 vs 19.8%, p = 0.02) with primary tumor. However, the extent of axillary staging did not affect systemic or radiation recommendations. In the subgroup of patients without previous ALND, the clinicopathologic characteristics were roughly comparable. No significant differences were observed in LRRFS, DMFS or OS between the two groups. CONCLUSION: For node-negative IBTR patients, we observed selection bias on the basis of prior ALND, shorter recurrence interval, and concordant molecular subtype favoring no SAS but comparable LRRFS, DMFS, and OS. These results support a wider consideration of sparing SAS in the management of IBTR, especially in patients without previous ALND.


Assuntos
Neoplasias da Mama , Mastectomia Segmentar , Neoplasias da Mama/patologia , Feminino , Humanos , Mastectomia , Mastectomia Segmentar/efeitos adversos , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos
17.
Mol Cell Biochem ; 477(11): 2493-2505, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35588343

RESUMO

This study aimed to investigate the role of cancer-associated fibroblast (CAF)-derived midkine (MK) in cisplatin (DDP) resistance. The primary cultures of CAFs and non-cancer fibroblasts (NFs) were isolated and purified. The DDP-resistant gastric cancer (GC) cells were cultured with CAF-conditioned medium. QRT-PCR and Elisa assays were employed to determine MK expression. The expression of ST7-AS1 was measured by qRT-PCR. The impact of CAFs, MK, and ST7-AS1 silencing on DDP resistance was determined by MTT and Annexin V/PI staining assay. Expression of EMT markers and PI3K/AKT was determined by Western blot and qRT-PCR. The role of MK in DDP resistance was confirmed in a xenograft model. Incubation with CAF-conditioned medium increased the IC50 to DDP. Also, incubation with CAF-conditioned medium increased cell viability, reduced cell apoptosis, and promoted EMT in DDP-resistant GC cells, which were all blocked with MK neutralization antibody treatment. MK increased the DDP resistance and upregulated the expression of ST7-AS1 in DDP-resistant GC cells. Additionally, ST7-AS1 knockdown increased the sensitivity to DDP by inhibiting EMT. Moreover, ST7-AS1 knockdown significantly decreased the phosphorylation of PI3K and AKT, and suppressed EMT, which were restored by MK addition. Finally, MK promoted tumor growth and DDP resistance in a mice model bearing the SGC-7901/DDP xenografts. CAF-derived MK promotes EMT-mediated DDP resistance via upregulation of ST7-AS1 and activation of PI3K/AKT pathway.


Assuntos
Fibroblastos Associados a Câncer , Transição Epitelial-Mesenquimal , Midkina , RNA Longo não Codificante , Neoplasias Gástricas , Animais , Humanos , Camundongos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Meios de Cultivo Condicionados/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Midkina/genética , Midkina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
18.
Intervirology ; 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36103866

RESUMO

The novel coronavirus (COVID-19 or 2019-nCoV) is a respiratory virus that can exist in the mouth and saliva of patients and spreads through aerosol dispersion. Therefore, stomatological hospitals and departments have become high-infection-risk environments. Accordingly, oral disinfectants that can effectively inactivate the virus have become a highly active area of research. Hexadecyl pyridinium chloride, povidone-iodine, and other common oral disinfectants are the natural primary choices for stomatological hospitals. Therefore, this study investigated the inhibitory effect of hexadecyl pyridinium chloride on SARS-CoV-2 in vitro. Vero cells infected with SARS-CoV-2 were used to determine the disinfection effect; the CCK-8 method was used to determine cytotoxicity, and viral load was determined by real-time PCR. The results showed that hexadecyl pyridinium chloride has no obvious cytotoxic effect on Vero cells in the concentration range 0.0125-0.05 mg/mL. The in vitro experiments showed that hexadecyl pyridinium chloride significantly inhibits the virus at concentrations of 0.1 mg/mL or above at 2 min of action. Thus, the results provide experimental support for the use of hexadecyl pyridinium chloride in stomatological hospitals.

19.
Int J Mol Sci ; 23(16)2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-36012608

RESUMO

Amines play an important role in synthesizing drugs, pesticides, dyes, etc. Herein, we report on an efficient catalyst for the general construction of amine mediated by nickel boride nanoclusters supported by a TS-1 molecular sieve. Efficient production of amines was achieved via catalytic hydrogenation of N=X (X = C, O, H) bonds. In addition, the catalyst maintains excellent performance upon recycling. Compared with the previous reports, the high activity, simple preparation and reusability of the Ni-B catalyst in this work make it promising for industrial application in the production of amines.


Assuntos
Aminas , Boranos , Aminação , Aminas/química , Catálise , Níquel/química
20.
Breast Cancer Res Treat ; 185(2): 371-380, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32975708

RESUMO

PURPOSE: Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy. METHODS: In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB-IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group. RESULTS: 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011). CONCLUSIONS: Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Epirubicina , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Ciclofosfamida/uso terapêutico , Epirubicina/uso terapêutico , Feminino , Humanos , Proteínas de Membrana , Paclitaxel/efeitos adversos , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico , Resultado do Tratamento , Vinorelbina/uso terapêutico
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