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Objective: Observational studies showed that Type 2 diabetes increased the risk of breast cancer, and vice versa. However, it is uncertain whether the link is causal or just due to confounding factors. Using bidirectional Mendelian randomization analysis, we assessed the bidirectional causal relationship from a genetic level. Methods: Large genome-wide association studies yielded summary-level data for Type 2 diabetes and breast cancer. Results: Genetically predicted Type 2 diabetes presented no statistically significant association with overall breast cancer or its subtypes. Similarly, genetically predicted overall breast cancer or its subtypes had no causal effect on Type 2 diabetes. Sensitivity analyses yielded similar results. Conclusion: Our bidirectional Mendelian randomization studies revealed no causal links between Type 2 diabetes and breast cancer.
[Box: see text].
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Neoplasias da Mama , Diabetes Mellitus Tipo 2 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/etiologia , Neoplasias da Mama/epidemiologia , Feminino , Fatores de Risco , CausalidadeRESUMO
Anlotinib, a multitarget tyrosine kinase inhibitor, can inhibit tumour angiogenesis proliferation, metastasis, promote vascular normalization, increase T cell and NK cell activity and infiltration, remodel tumour microenvironment and synergistic immune enhancement. Our study aimes to evaluate the efficacy of anlotinib in the treatment of advanced metastatic breast cancer (MBC) after multiple lines of therapy. Patients included were treated with anlotinib for advanced MBC in the Affiliated Cancer Hospital of Zhengzhou University from 1 January 2019 to 30 June 2023. The objective remission rate, disease-free progression survival and adverse reactions were analysed. We compared and analysed the efficacy of anlotinib in the treatment of advanced metastatic breast cancer, which showed that ORR was 23.6% and DCR was 69.1%. The DCR of monotherapy was 66.7% and that of combination therapy was 69.6% in MBC patients. The combination therapy, combined with chemotherapy had the best effect (79.3%), combined with immunotherapy came second. In addition, the DCR (88.9%) was higher in MBC patients having received prior antiangiogenic therapy. According to the Kaplan-Meier (K-M) survival estimate analysis, the mPFS was 4.17 months (95% CI, 1.758-6.582 months) in Her-2 positive MBC patients, and 7.83 months (95% CI, 2.416-9.104) in Her-2 negative MBC patients. The mPFS was 5.76 months (95% CI, 3.231-8.298 m) in HR positive MBC patients, 7.83 months (95% CI, 3.182-12.478 m) in TNBC patients. Fatigue (20.0%), hypertension (21.8%) and liver dysfunction (18.2%) were common adverse reactions, followed by bone marrow suppression (16.4%), anorexia (14.5%), hypothyroidism (14.5%) and diarrhoea (14.5%). Altogether, Anlotinib monotherapy or combination therapy provides a viable third (or above)-line therapeutic strategy in patients with metastatic breast cancer. The adverse reactions of anlotinib are well tolerated and controllable.
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Ferroptosis is distinct from classic apoptotic cell death characterized by the accumulation of reactive oxygen species (ROS) and lipid peroxides on the cell membrane. Increasing findings have demonstrated that ferroptosis plays an important role in cancer development, but the exploration of ferroptosis in breast cancer is limited. In our study, we aimed to establish a ferroptosis activation-related model based on the differentially expressed genes between a group exhibiting high ferroptosis activation and a group exhibiting low ferroptosis activation. By using machine learning to establish the model, we verified the accuracy and efficiency of our model in The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) set and gene expression omnibus (GEO) dataset. Additionally, our research innovatively utilized single-cell RNA sequencing data to systematically reveal the microenvironment in the high and low FeAS groups, which demonstrated differences between the two groups from comprehensive aspects, including the activation condition of transcription factors, cell pseudotime features, cell communication, immune infiltration, chemotherapy efficiency, and potential drug resistance. In conclusion, different ferroptosis activation levels play a vital role in influencing the outcome of breast cancer patients and altering the tumor microenvironment in different molecular aspects. By analyzing differences in ferroptosis activation levels, our risk model is characterized by a good prognostic capacity in assessing the outcome of breast cancer patients, and the risk score can be used to prompt clinical treatment to prevent potential drug resistance. By identifying the different tumor microenvironment landscapes between the high- and low-risk groups, our risk model provides molecular insight into ferroptosis in breast cancer patients.
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Carcinoma , Ferroptose , Humanos , Ferroptose/genética , Apoptose , Fenótipo , Análise de Sequência de RNA , Microambiente TumoralRESUMO
BACKGROUND: Fatty acid synthase (FASN) is a lipogenic enzyme that participates in tumor progression. We previously showed that FASN is dysregulated in OS malignancy, but the molecular mechanism(s) of these effects remained unclear. METHODS: We examined differentially expressed proteins (DEPs) in FASN-silenced osteosarcoma 143B cells and their parental cells by isobaric tags for relative and absolute quantitation (iTRAQ). Differentially expressed proteins were classified using GO and KEGG analysis. The association between FASN and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) was confirmed using qPCR, Western blot, and immunohistochemistry. The function of HNRNPA1 in osteosarcoma was determined using CCK-8, colony formation, wound healing, transwell migration, and invasion assays. RESULTS: Among the 4971 identified proteins, 567 DEPs (325 upregulated and 242 downregulated) were identified. The top 10 upregulated proteins comprised HIST1H2AB, INA, INTS5, MTCH2, EIF1, MAPK1IP1L, PXK, RPS27, PM20D2, and ZNF800, while the top 10 downregulated proteins comprised NDRG1, CNTLN, STON2, GDF7, HECTD3, HBB, TPM1, PPP4R4, PTTG1IP, and PLCB3. Bioinformatic analysis indicated that the DEPs were related to cellular processes, metabolic processes, biological regulation, binding, and catalytic activity. HNRNPA1 was dysregulated in FASN-silenced 143B and HOS cells. qPCR, Western blot, and immunohistochemistry showed that FASN expression positively correlates with HNRNPA1 expression. Further studies indicated that HNRNPA1 correlates with OS diagnosis and prognosis. And HNRNPA1 silence inhibits the proliferation, migration, and invasion in OS cells. CONCLUSION: HNRNPA1 acts as targets downstream of FASN and potential biomarker and oncogene in OS.
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Neoplasias Ósseas/metabolismo , Ácido Graxo Sintase Tipo I/metabolismo , Osteossarcoma/metabolismo , Proteômica/métodos , Adulto , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ácido Graxo Sintase Tipo I/genética , Feminino , Ontologia Genética , Ribonucleoproteína Nuclear Heterogênea A1/genética , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Humanos , Masculino , Osteossarcoma/genética , Osteossarcoma/patologia , Adulto JovemRESUMO
Aims: Programmed death-1 (PD-1) blockade is a vital therapy for solid tumors, but not all patients benefit. Identifying which patients will benefit from immunotherapy is a key focus in oncology research. Patients & Methods: This study analyzed the correlation between the number of peripheral lymphocytes and the efficacy and prognosis of immunotherapy in advanced malignant melanoma. Results: Patients with a partial response had significantly lower peripheral B cell levels, and patients with a lower number of B lymphocytes had a longer survival time. Conclusion: These results suggest that peripheral B cells are correlated with the efficacy of PD-1 antibody and prognosis and are thus potential biomarkers for the efficacy and prognosis of PD-1 antibody immunotherapy in malignant melanoma.
Immunotherapy is an important treatment for cancer patients with solid tumors. Because immunotherapy does not work equally well for everybody, an important area of research is to determine for which patients the treatment will work. Our study focused on skin cancer patients. We examined the relationship between the number of B cells (a type of immune cell) in patients' blood, and how well they responded to immunotherapy. We observed that patients who partially responded to treatment had lower levels of B cells. Additionally, patients who had a lower number of B cells also had a longer survival time. This could mean that looking at patients' B cell levels might be useful in working out how well they well respond to immunotherapy.
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Melanoma , Neoplasias Cutâneas , Humanos , Receptor de Morte Celular Programada 1 , Neoplasias Cutâneas/patologia , Imunoterapia/métodos , Linfócitos B/patologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (AR), the root of Astragalus membranaceus (Fisch.) Bge. or Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, known as Huangqi in traditional Chinese medicine, has been widely used in traditional Chinese medicine prescriptions for acute and chronic liver injury. AR was the most important medicine in a Chinese traditional prescription called Huangqi Decoction (HQD), has been used to treat chronic liver diseases since the 11th century. In particular, its major active ingredient, Astragalus polysaccharide (APS), has demonstrated promising effects on inhibiting hepatic fibrosis. However, to date, the effect of APS against alcohol-induced hepatic fibrosis and its underlying molecular mechanisms remains unknown. AIMS OF THE STUDY: This study aimed to explore the effect and potential molecular mechanisms of APS against alcohol-induced hepatic fibrosis by using network pharmacology and experimental validation. MATERIALS AND METHODS: The potential targets and underling mechanism of AR in alcoholic liver fibrosis were first predicted using network pharmacology, followed by experimental validation using SD rat model with alcohol-induced hepatic fibrosis. Further, the predicted candidate signaling pathways and potential target polymerase I and transcript release factor (PTRF) were combined to explore the multifaceted mechanism of APS against alcohol-induced hepatic fibrosis. Finally, overexpression of PTRF was explored to reveal the role of PTRF in the mechanism of APS against alcohol-induced hepatic fibrosis. RESULT: APS exerted potent anti-hepatic fibrosis effects by downregulating genes involved in the Toll-like receptor 4 (TLR4)/JNK/NF-κB/MyD88 pathway. Notably, APS treatment ameliorated the hepatic damage by inhibiting the overexpression of PTRF and decreasing the co-localisation of TLR4/PTRF. Overexpression of PTRF induced reversal of the protective effects of APS on alcohol-induced hepatic fibrosis. CONCLUSION: This study indicated that APS may alleviate alcohol-induced hepatic fibrosis by inhibiting the activation of PTRF and TLR4/JNK/NF-κB/MyD88 pathway, which provides a scientific elucidation for the mechanisms of APS on the anti-hepatic fibrosis activity and presents a promising therapeutic approach for treating hepatic fibrosis.
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Astrágalo , NF-kappa B , Ratos , Animais , NF-kappa B/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/metabolismo , Ratos Sprague-Dawley , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Polissacarídeos/farmacologiaRESUMO
Akkermansia muciniphila (A. muciniphila), a gram-negative anaerobic bacterium, is selectively decreased in the fecal microbiota of patients with colorectal cancer (CRC), but its molecular mechanism in CRC development remains inconclusive. In this study, we first confirmed the inhibitory effect of A. muciniphila on CRC formation and analyzed the metabolic role of intestinal flora in human Polyps, A-CRA (advanced colorectal adenoma) and CRC samples. To better clarify the role of A. muciniphila in CRC development, a pseudo-germ-free (GF) azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model was established, followed by infection with or without A. muciniphila. Metabolomic analysis and RNA-seq analysis showed tryptophan-mediated aryl hydrocarbon receptor (AhR) was significantly down-regulated in A. muciniphila-infected CRC mice. Then, mice with intestinal specific AhR deficiency (AhRfl/fl Cre) were generated and were used in 2 murine models: AOM/DSS treatment as a model of carcinogen-induced colon cancer and a genetically induced model using ApcMin/+ mice. Notably, AhR deficiency inhibited CRC growth in the AOM/DSS and ApcMin/+ mouse model. Moreover, AhR deficiency inhibited, rather than enhanced, tumor formation and tumor-derived organoids in Apc-deficient cells both in vivo and in vitro by activating Wnt/ß-catenin signaling and TCF4/LEF1-dependent transcription. Furthermore, the antitumor effectiveness of A. muciniphila was abolished either in a human colon cancer tumor model induced by subcutaneous transplantation of AhR-silenced CRC cells, or AhR-deficienty spontaneous colorectal cancer model. In conclusion, supplementation with A. muciniphila. protected mice from CRC development by specifically inhibiting tryptophan-mediated AhR/ß-catenin signaling.
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Neoplasias do Colo , Neoplasias Colorretais , Humanos , Camundongos , Animais , beta Catenina/metabolismo , Triptofano/efeitos adversos , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Composição de Bases , Filogenia , RNA Ribossômico 16S , Análise de Sequência de DNA , Neoplasias Colorretais/metabolismo , Via de Sinalização Wnt , Camundongos Endogâmicos C57BLRESUMO
Long noncoding RNAs (lncRNAs) play crucial roles in regulating a variety of biological processes in lung adenocarcinoma (LUAD). In our study, we mainly explored the functional roles of a novel lncRNA long intergenic non-protein coding RNA 1426 (LINC01426) in LUAD. We applied bioinformatics analysis to find the expression of LINC01426 was upregulated in LUAD tissue. Functionally, silencing of LINC01426 obviously suppressed the proliferation, migration, epithelial-mesenchymal transition (EMT), and stemness of LUAD cells. Then, we observed that LINC01426 functioned through the hedgehog pathway in LUAD. The effect of LINC01426 knockdown could be fully reversed by adding hedgehog pathway activator SAG. In addition, we proved that LINC01426 could not affect SHH transcription and its mRNA level. Pull-down sliver staining and RIP assay revealed that LINC01426 could interact with USP22. Ubiquitination assays manifested that LINC01426 and USP22 modulated SHH ubiquitination levels. Rescue assays verified that SHH overexpression rescued the cell growth, migration, and stemness suppressed by LINC01426 silencing. In conclusion, LINC01426 promotes LUAD progression by recruiting USP22 to stabilize SHH protein and thus activate the hedgehog pathway.
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Adenocarcinoma de Pulmão/metabolismo , Proteínas Hedgehog/metabolismo , Neoplasias Pulmonares/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Células-Tronco Neoplásicas/patologia , Fenótipo , Proteólise , RNA Longo não Codificante/genética , Transdução de Sinais , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação , Regulação para CimaRESUMO
OBJECTIVE: To compare and analyze three therapies on patients with primary central nervous system lymphoma (PCNSL), aiming to provide evidences for future treatment and prognosis. METHODS: Clinical data of 26 cases of PCNSL with normal immune system confirmed by postoperative pathology were retrospectively analyzed. Among them there were six cases with operation only, nine cases with operation and radiotherapy, and 11 cases with operation, radiotherapy and chemotherapy, and their survival rate was compared as well. RESULTS: The survival time of patients with operation only, operation combined with radiotherapy and operation combined with radiotherapy and chemotherapy was 6-11â¯months, 15-24â¯months and 24-51â¯months, respectively. And their median survival time was only nine months, 21â¯months and 38â¯months, respectively. CONCLUSIONS: Operation combined with radiotherapy and chemotherapy can dramatically extend PCNSL patients' survival time, therefore, it can be regarded as the first-line therapy.
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Recent epidemiological and preclinical studies have revealed that aspirin possesses antitumor properties; one of the mechanisms results from inhibition of angiogenesis. However, the underlying mechanisms of such action remain to be elucidated, in particular, the effect of aspirin on glucose metabolism of vascular endothelial cells (ECs) has not yet been reported. Herein, we demonstrate that glucose transporter 1 (GLUT1), a main glucose transporter in ECs, can be down-regulated by aspirin. Exposure to 4-mM aspirin significantly decreased GLUT1 at the mRNA and protein level, resulting in impaired glucose uptake capacity in vascular ECs. In addition, we also showed that exposure to 4-mM aspirin led to an inhibition of intracellular ATP and lactate synthesis in vascular ECs, and a down-regulation of the phosphorylation level of NF-κB p65 was observed. Taken together, these findings indicate 4-mM aspirin inhibits glucose uptake and glucose metabolism of vascular ECs through down-regulating GLUT1 expression and suggest that GLUT1 has potential to be a target for aspirin in vascular ECs.