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AIMS: Compared to primary breast sarcoma (BSs), radiotherapy-induced sarcoma (RIS) is a less frequent type of secondary breast sarcoma. Undifferentiated pleomorphic sarcoma (UPS) is an even rarer occurrence within the RIS category. This study aimed to present the clinicopathologic and molecular features of breast radiotherapy-induced UPS. METHODS: A retrospective study was conducted at the Third Affiliated Hospital of Soochow University to analyze three patients with radiation-induced undifferentiated pleomorphic sarcoma (UPS) following breast cancer, spanning from 2006 to 2023. The clinical and pathological variables were extracted from the medical records, while immunohistochemistry was employed to analyze the immunophenotypes of these tumors. Genomic characteristics were assessed through DNA and RNA sequencing techniques. Another 15 cases from the literature were also reviewed to better characterize the tumor. RESULTS: The affected areas encompass the chest wall and breasts, with an incubation period ranging from 6 to 17 years. The tumor cells exhibit pleomorphism and demonstrate a high degree of pathological mitosis. Notably, two cases displayed an accelerated disease progression, characterized by recurrent tumors and metastases occurring within short intervals of 48 and 7 months respectively subsequent to the initial diagnosis. The two prevailing identified genes were TP53 (2/3, 66.7%) and RB1 (1/3, 33.3%). Through analysis of somatic copy number variation (CNV), it was discovered that two oncogenes, MCL1 (1/3, 33.3%) and MYC (1/3, 33.3%), had experienced gains in CNV. The Tumor Mutational Burden (TMB) values for case 1, case 2, and case 3 were 5.9 mut/Mb, 1.0 mut/Mb, and 3.0 mut/Mb, respectively. Moreover, the analysis of RNA-NGS (next-generation sequencing) revealed the presence of a novel gene fusion, named COL3A1-GULP1, in case 2. CONCLUSIONS: Based on our thorough analysis of research findings and previous reports, it is evident that radiotherapy-induced UPS exhibits a highly diverse and frequently severe clinical and biological behavior. Identifying tumor formation using genome sequencing can help understand its biological behavior and determine personalized treatments.
Subject(s)
Breast Neoplasms , Neoplasms, Radiation-Induced , Sarcoma , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Sarcoma/genetics , Sarcoma/pathology , Neoplasms, Radiation-Induced/genetics , Neoplasms, Radiation-Induced/pathology , Middle Aged , Retrospective Studies , Adult , Biomarkers, Tumor/genetics , Aged , Retinoblastoma Binding Proteins/genetics , Ubiquitin-Protein LigasesABSTRACT
CONTEXT: Both physical activity (PA) and sedentary behavior (SB) exert important impact on type 2 diabetes, but it remains unclear how maximum impact on improving the mortality and optimized proportion of the two lifestyles combination exists. OBJECTIVE: To explore the impacts of PA/SB combinations on mortality in patients with diabetes. METHODS: Patients with type 2 diabetes patients samplings were collected from the National Health and Nutrition Examination Survey (NHANES) dataset. Their lifestyles were categorized into eight groups based on combinations of the PA and SB levels. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals. RESULTS: During the follow-up period, 1,148 deaths (18.94%) were recorded. High SB (sedentary time ≥6 hours/day) was significantly associated with higher all-cause mortality (HR 1.65). In participants with low SB (<6 hours/day), low PA was associated with lower all-cause mortality (HR 0.43), while further increase of PA level did not show further reduction in either all-cause or cardiovascular mortality. In contrast, in participants with high SBï¼all levels of PA were associated with lower all-cause mortality (p<0.05), but only moderate PA was associated with lower cardiovascular mortality (HR 0.30). CONCLUSIONS: In patients with type 2 diabetes, different combinations of various levels of PA and SB are associated with different degree of risk for all-cause or cardiovascular mortality.
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Introduction: Triple-negative breast cancer (TNBC) is characterized by its aggressive nature and absence of specific therapeutic targets, necessitating the reliance on chemotherapy as the primary treatment modality. However, the drug resistance poses a significant challenge in the management of TNBC. In this study, we investigated the role of DDX58 (DExD/H-box helicase 58), also known as RIG-I, in TNBC chemoresistance. Methods: The relationship between DDX58 expression and breast cancer prognosis was investigated by online clinical databases and confirmed by immunohistochemistry analysis. DDX58 was knockout by CRISPR-Cas9 system (DDX58-KO), knockdown by DDX58-siRNA (DDX58-KD), and stably over expressed (DDX58-OE) by lentivirus. Western blotting, immunofluorescence and qPCR were used for related molecules detection. Apoptosis was analyzed through flow cytometry (Annexin V/7AAD apoptosis assay) and Caspase 3/7 activity assay. Results: Patients with lower expression of DDX58 led to lower rate of pathological complete response (pCR) and worse prognosis by online databases and hospital clinical data. DDX58-KD cells showed multiple chemo-drugs resistance (paclitaxel, doxorubicin, 5-fluorouracil) in TNBC cell lines. Similarly, DDX58-KO cells also showed multiple chemo-drugs resistance in a dosage-dependent manner. In the CDX model, tumours in the DDX58-KO group had a 25% reduction in the tumour growth inhibition rate (IR) compared to wild-type (WT) group after doxorubicin (Dox) treatment. The depletion of DDX58 inhibited proliferation and promoted the migration and invasion in MDA-MB-231 cells. The findings of our research indicated that DDX58-KO cells exhibit a reduction in Dox-induced apoptosis both in vivo and in vitro. Mechanistically, Dox treatment leads to a significant increase in the expression of double-stranded RNAs (dsRNAs) and activates the DDX58-Type I interferon (IFN) signaling pathway, ultimately promoting apoptosis in TNBC cells. Discussion: In the process of TNBC chemotherapy, the deficiency of DDX58 can inhibit Dox-induced apoptosis, revealing a new pathway of chemotherapy resistance, and providing a possibility for developing personalized treatment strategies based on DDX58 expression levels.
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BACKGROUND: Chemotherapy is a primary treatment for breast cancer (BC), yet many patients develop resistance over time. This study aims to identify critical factors contributing to chemoresistance and their underlying molecular mechanisms, with a focus on reversing this resistance. METHODS: We utilized samples from the Gene Expression Omnibus (GEO) and West China Hospital to identify and validate genes associated with chemoresistance. Functional studies were conducted using MDA-MB-231 and MCF-7 cell lines, involving gain-of-function and loss-of-function approaches. RNA sequencing (RNA-seq) identified potential mechanisms. We examined interactions between DNAJC12, HSP70, and AKT using co-immunoprecipitation (Co-IP) assays and established cell line-derived xenograft (CDX) models for in vivo validations. RESULTS: Boruta analysis of four GEO datasets identified DNAJC12 as highly significant. Patients with high DNAJC12 expression showed an 8 % pathological complete response (pCR) rate, compared to 38 % in the low expression group. DNAJC12 inhibited doxorubicin (DOX)-induced cell death through both ferroptosis and apoptosis. Combining apoptosis and ferroptosis inhibitors completely reversed DOX resistance caused by DNAJC12 overexpression. RNA-seq suggested that DNAJC12 overexpression activated the PI3K-AKT pathway. Inhibition of AKT reversed the DOX resistance induced by DNAJC12, including reduced apoptosis and ferroptosis, restoration of cleaved caspase 3, and decreased GPX4 and SLC7A11 levels. Additionally, DNAJC12 was found to increase AKT phosphorylation in an HSP70-dependent manner, and inhibiting HSP70 also reversed the DOX resistance. In vivo studies confirmed that AKT inhibition reversed DNAJC12-induced DOX resistance in the CDX model. CONCLUSION: DNAJC12 expression is closely linked to chemoresistance in BC. The DNAJC12-HSP70-AKT signaling axis is crucial in mediating resistance to chemotherapy by suppressing DOX-induced ferroptosis and apoptosis. Our findings suggest that targeting AKT and HSP70 activities may offer new therapeutic strategies to overcome chemoresistance in BC.
Subject(s)
Breast Neoplasms , Ferroptosis , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/genetics , Ferroptosis/genetics , Drug Resistance, Neoplasm/genetics , Doxorubicin/pharmacology , MCF-7 Cells , Apoptosis , Cell Line, TumorABSTRACT
INTRODUCTION: Surgical ventricular reconstruction (SVR) is an alternative therapeutic approach in patients with refractory heart failure (HF), but residual remodeling after SVR limits the improvement of HF. Recently, we reported that SVR may act as an environmental cue to reactivate endogenous proliferation of cardiomyocytes; however, it is unclear whether enhancing endogenous cardiomyocyte regeneration further improves HF after SVR. OBJECTIVES: We aimed to explore whether circular RNAs (circRNAs) would involved in SVR and their mechanisms. METHODS: Male C57BL/6 mice were subjected to myocardial infarction (MI) or sham surgery. Four weeks later, MI mice with a large ventricular aneurysm underwent SVR or a second open-chest operation only. Echocardiography and histological analysis were used to evaluate heart function, cardiac remodeling, and myocardial regeneration. Sequencing of circular RNAs, RNA immunoprecipitation, RNA pulldown, and luciferase reporter assay were used to explore the underlying mechanisms. RESULTS: SVR markedly attenuated cardiac remodeling and induced cardiomyocyte regeneration, as evidenced by positive staining of Ki-67, phospho-histone H3 (pH3), and Aurora B in the plication zone, but significant residual remodeling still existed in comparison with the sham group. Sequencing results showed that SVR altered the expression profile of cardiac circRNAs, and circMap4k2 was identified as the most upregulated one. After characterizing circMap4k2, we noted that overexpression of circMap4k2 significantly promoted proliferation of cardiomyocytes in cultured neonatal rat cardiomyocytes and silencing of circMap4k2 significantly inhibited it; similar results were obtained in SVR-treated MI mice but not in MI mice without SVR treatment. Residual cardiac remodeling after SVR was further attenuated by circMap4k2 overexpression. CircMap4k2 bound with miR-106a-3p and inhibited cardiomyocyte proliferation by targeting a downstream effector of the antizyme inhibitor 1 (Azin1) gene. CONCLUSIONS: CircMap4k2 acts as an environmental cue and targets the miR-106a-3p/Azin1 pathway to increase cardiac regeneration in the plication zone and attenuate residual remodeling after SVR.
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Previous studies show a woman's pregnancy is correlated with post-reproductive longevity, and nulliparity is associated with higher risk of incident heart failure, suggesting pregnancy likely exerts a cardioprotection. We previously reported a cardioprotective phenomenon termed myocardial hypertrophic preconditioning, but it is unknown whether pregnancy-induced physiological hypertrophic preconditioning (PHP) can also protect the heart against subsequent pathological hypertrophic stress. We aimed to clarify the phenomenon of PHP and its mechanisms. The pluripara mice whose pregnancy-induced physiological hypertrophy regressed and the nulliparous mice underwent angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Echocardiography, invasive left ventricular hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. Silencing or overexpression of Foxo3 by adeno-associated virus was used to investigate the role of FoxO3a involved in the antihypertrophic effect. Compared with nulliparous mice, pathological cardiac hypertrophy induced by Ang II infusion, or TAC was significantly attenuated and heart failure induced by TAC was markedly improved in mice with PHP. Activation of FoxO3a was significantly enhanced in the hearts of postpartum mice. FoxO3a inhibited myocardial hypertrophy by suppressing signaling pathway of phosphorylated glycogen synthase kinase-3ß (p-GSK3ß)/ß-catenin/Cyclin D1. Silencing or overexpression of Foxo3 attenuated or enhanced the anti-hypertrophic effect of PHP in mice with pathological stimulation. Our findings demonstrate that PHP confers resistance to subsequent hypertrophic stress and slows progression to heart failure through activation of FoxO3a/GSK3ß pathway.
Subject(s)
Aortic Valve Stenosis , Heart Failure , Peptide Hormones , Animals , Female , Mice , Pregnancy , Angiotensin II , Cardiomegaly/genetics , Glycogen Synthase Kinase 3 beta/genetics , HeartABSTRACT
Systemic and pulmonary arterial hypertension (PAH) can induce left and right ventricular hypertrophy, respectively, but common therapeutic targets for both left and right hypertrophy are limited. In this study, we attempt to explore potential common therapeutic targets and screen out potential target drugs for further study. Cardiac mRNA expression profiles in mice with transverse aortic constriction (TAC) and pulmonary arterial constriction (PAC) are obtained from online databases. After bioinformatics analyses, we generate TAC and PAC mouse models to validate the phenotypes of cardiac remodelling as well as the identified hub genes. Bioinformatics analyses show that there are 214 independent differentially expressed genes (DEGs) in GSE136308 (TAC related) and 2607 independent DEGs in GSE30922 (PAC related), while 547 shared DEGs are associated with the function of the extracellular matrix (ECM) or involved in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and ECM-receptor interactions. We identifyd Fn1, Il6, Col1a1, Igf1, Col1a2, Timp1, Col3a1, Cd44, Ctgf and Postn as hub genes of the shared DEGs, and most of them are associated with myocardial fibrosis. Those hub genes and phenotypes of cardiac remodelling are validated in our TAC and PAC mouse models. Furthermore, we identify dehydroisoandrosterone (DHEA), iloprost and 4,5-dianilinophthalimide (DAPH) as potential therapeutic drugs targeting both left and right ventricular hypertrophy and validate the effect of DHEA. These findings suggest that DHEA could be an effective drug for pressure overload-induced left or right ventricular hypertrophy by regulating the shared hub differentially expressed genes associated with fibrosis.
Subject(s)
Hypertrophy, Left Ventricular , Pulmonary Arterial Hypertension , Mice , Animals , Hypertrophy, Left Ventricular/genetics , Hypertrophy, Left Ventricular/metabolism , Hypertrophy, Right Ventricular/genetics , Pulmonary Arterial Hypertension/etiology , Pulmonary Arterial Hypertension/genetics , Ventricular Remodeling , Phosphatidylinositol 3-Kinases , Cardiomegaly , Computational Biology , Dehydroepiandrosterone , Fibrosis , Mice, Inbred C57BLABSTRACT
BACKGROUND: Right ventricular (RV) function is a major prognostic factor in patients with cardiopulmonary disease. Effective medical therapies are available for left heart failure, but they are usually less effective or even ineffective in right heart failure. Here, we tested the hypothesis that LCZ696 (sacubitril/valsartan) can attenuate pressure overload-induced RV remodeling by inhibiting pyruvate dehydrogenase kinase 4 (PDK4). METHODS: Adult male C57 mice were subjected to transverse aortic constriction (TAC), pulmonary artery constriction (PAC), or sham surgery. Bioinformatics analysis was used to screen for common differentially expressed genes (DEGs) between TAC and PAC. Chemical compounds targeting DEGs were predicted by molecular docking analysis. Effects of LCZ696 on PAC-induced RV remodeling and the associated PDK4-related mechanisms were investigated. RESULTS: We found 60 common DEGs between PAC and TAC, and Pdk4 was one of the downregulated DEGs. From 47 chemical compounds with potential cardiovascular activity and PDK4 protein binding ability, we selected LCZ696 to treat PAC-induced RV remodeling because of its high docking score for binding PDK4. Compared with vehicle-treated PAC mice, LCZ696-treated mice had significantly smaller RV wall thickness and RV diameters, less myocardial fibrosis, lower expression of PDK4 protein, and less phosphorylation of glycogen synthase kinase-3ß (p-GSK3ß). In PAC mice, overexpression of Pdk4 blocked the inhibitory effect of LCZ696 on RV remodeling, whereas conditional knockout of Pdk4 attenuated PAC-induced RV remodeling. CONCLUSIONS: Pdk4 is a common therapeutic target for pressure overload-induced left ventricular and RV remodeling, and LCZ696 attenuates RV remodeling by downregulating Pdk4 and inhibiting PDK4/p-GSK3ß signal.
Subject(s)
Heart Failure , Hypertension, Pulmonary , Male , Mice , Animals , Hypertension, Pulmonary/drug therapy , Glycogen Synthase Kinase 3 beta , Ventricular Remodeling , Molecular Docking Simulation , Valsartan/therapeutic use , Biphenyl Compounds/therapeutic use , Drug Combinations , Disease Models, AnimalABSTRACT
BACKGROUND: The genomic landscape of breast malignant phyllodes tumors (PTs) is not well defined, especially pregnancy-related malignant PTs. To clarify this topic, whole-exome next-generation sequencing (NGS) was performed on tumor samples and paired normal breast tissues from two pregnancy-related malignant PTs, followed by a functional analysis of the genetic alterations. METHODS: DNA from malignant PT samples and matched normal breast tissues of both patients were subjected to molecular profiling. NGS of the whole-exome was performed in a commercial molecular pathology laboratory. Predictive tools were used to estimate genetic variation in somatic and germline genes. RESULTS: In total, 29 somatic genomic alterations and 18 germline alterations were found in both patients. In Patient 1, 12 aberrations were identified in the tumor tissue, and 9 alterations were identified in matched normal breast tissue. One pathogenic variant in tumor suppressor genes (TP53) was detected in patient 1. In Patient 2, 18 and 10 variants were found in the tumor and matched normal breast tissue, respectively. In Patient 2, pathogenic alterations were identified in two tumor suppressor genes (PTEN and TP53). PTEN and TP53 may be potential drug targets. The functional predictive tools showed that genes of unknown significance for PTs, including FCHO1 in Patient 1, and LRP12 and PKM in Patient 2, were pathogenic. Several genes, including FCHO1, LRP12 and PKM, were shown for the first time to be altered in malignant PTs. A potentially pathogenic germline variant in PRF1, was detected in Patient 1. CONCLUSION: Our study first demonstrated somatic and germline gene alterations in two malignant PTs during pregnancy and lactation. These two PTs shared major genetic events, including TP53 mutation, which commonly occurs in malignant PTs; additionally, we identified two potential genes for targeted therapy, TP53 and PTEN. One germline mutation in PRF1 was also detected. These results provide clues regarding tumor pathogenesis and precision therapy development.
Subject(s)
Breast Neoplasms , Phyllodes Tumor , Female , Humans , Pregnancy , Phyllodes Tumor/genetics , Phyllodes Tumor/pathology , Exome Sequencing , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Genomics , Lactation , Membrane Proteins/geneticsABSTRACT
BACKGROUND: Severe heart failure refractory to conventional therapy requires alternative treatment modalities. Surgical ventricular reconstruction (SVR) has been used to reverse cardiac remodeling in post-myocardial infarction (MI) patients with large left ventricular (LV) aneurysm, however, residual LV remodeling and dysfunction remain postoperatively. It is unclear whether SVR recovers response to drug treatment and whether the sodium-glucose co-transporter 2 inhibitor dapagliflozin (DAPA) reverses residual LV remodeling after SVR. METHODS: Adult male C57 mice were subjected to MI or sham surgery. Four-week later, MI mice with LV aneurysm underwent modified SVR or second open-chest sham operation and were randomized to DAPA or vehicle for four-week. Cardiac remodeling, LV function, and the underlying mechanisms were evaluated by echocardiography, invasive LV hemodynamic measurements, mRNA sequencing, and bioinformatics analysis. RESULTS: SVR significantly decreased LV volume; increased myocardial strain, LV pressure change rates and end-systolic elastance; and decreased heart-to-body weight ratio and myocardial fibrosis. However, significant residual cardiac remodeling remained. DAPA significantly attenuated residual cardiac remodeling and improved LV function in SVR mice but did not have curative effects in non-SVR mice. Of the 1532 genes differentially expressed in SVR and MI mice, 1037 were associated with cardiac metabolism; Src, Crebbp, Fn1, Grb2, and Mapk14 were the top 5 hub genes. Unlike sham surgery, MI upregulated those 5 genes, and treatment with SVR + DAPA normalized their expression. CONCLUSIONS: SVR restores therapeutic response in the post-MI heart with large LV aneurysm, and DAPA attenuates residual cardiac remodeling after SVR by normalizing some cardiac metabolism-related hub genes.
Subject(s)
Aneurysm , Myocardial Infarction , Sodium-Glucose Transporter 2 Inhibitors , Animals , Male , Mice , Aneurysm/complications , Aneurysm/metabolism , Cardiomegaly/metabolism , Myocardium/metabolism , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Ventricular RemodelingABSTRACT
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with highly heterogeneous clinical symptoms and severity. There is complex pathogenesis of SLE, one of which is IFNs overproduction and downstream IFN-stimulated genes (ISGs) upregulation. Identifying the key ISGs differentially expressed in peripheral blood mononuclear cells (PBMCs) of patients with SLE and healthy people could help to further understand the role of the IFN pathway in SLE and discover potential diagnostic biomarkers. The differentially expressed ISGs (DEISG) in PBMCs of SLE patients and healthy persons were screened from two datasets of the Gene Expression Omnibus (GEO) database. A total of 67 DEISGs, including 6 long noncoding RNAs (lncRNAs) and 61 messenger RNAs (mRNAs) were identified by the "DESeq2" R package. According to Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, those DEISGs were mainly concentrated in the response to virus and immune system processes. Protein-protein interaction (PPI) network showed that most of these DEISGs could interact strongly with each other. Then, IFIT1, RSAD2, IFIT3, USP18, ISG15, OASL, MX1, OAS2, OAS3, and IFI44 were considered to be hub ISGs in SLE by "MCODE" and "Cytohubba" plugins of Cytoscape, Moreover, the results of expression correlation suggested that 3 lncRNAs (NRIR, FAM225A, and LY6E-DT) were closely related to the IFN pathway. The lncRNA NRIR and mRNAs (RSAD2, USP18, IFI44, and ISG15) were selected as candidate ISGs for verification. RT-qPCR results showed that PBMCs from SLE patients had substantially higher expression levels of 5 ISGs compared to healthy controls (HCs). Additionally, statistical analyses revealed that the expression levels of these ISGs were strongly associated to various clinical symptoms, including thrombocytopenia and facial erythema, as well as laboratory indications, including the white blood cell (WBC) count and levels of autoantibodies. The Receiver Operating Characteristic (ROC) curve demonstrated that the IFI44, USP18, RSAD2, and IFN score had good diagnostic capabilities of SLE. According to our study, SLE was associated with ISGs including NRIR, RSAD2, USP18, IFI44, and ISG15, which may contribute to the future diagnosis and new personalized targeted therapies.
Subject(s)
Interferon Type I , Lupus Erythematosus, Systemic , RNA, Long Noncoding , Antiviral Agents/metabolism , Humans , Interferon Type I/genetics , Interferon Type I/metabolism , Leukocytes, Mononuclear/metabolism , Lupus Erythematosus, Systemic/immunology , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Ubiquitin Thiolesterase/metabolismABSTRACT
BACKGROUND: We aimed to analyse the discrepancy in clinical features and prognosis between molecular subtypes in primary ductal carcinoma in situ (DCIS) patients with lumpectomy. METHODS: Primary DCIS patients were identified from the Surveillance, Epidemiology, and End Results registries database from 2010 to 2017. Based on immunohistochemistry markers of hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2), enrolled DCIS cases were divided into four molecular subtypes, HR-HER2-, HR-HER2+, HR + HER2+, and HR + HER2-. Clinical features and prognosis were compared between molecular subtypes. Radiotherapy (RT) effects on prognosis were also analysed in each molecular subtype. RESULTS: A total of 5,628 DCIS cases were retrospectively enrolled in this study. HR-HER2-, HR-HER2+, HR+HER2+, and HR+HER2- are 299 (5.3%), 498 (8.8%), 1,086 (19.3%), and 3,745 (66.5%), respectively. HR + HER2- cases have smaller tumor size (72.6%, P < 0.001) and lower grade (23.5%, P < 0.001). Comedo necrosis is more frequent in HR-HER2- (24.4%, P < 0.001) and HR-HER2+ DCIS cases (24.3%, P < 0.001). In univariate analyses, HR-HER2+ cases have significantly higher ipsilateral breast event (IBE) recurrence than HR+HER2- cases (P = 0.010). HR-HER2- cases show higher disease-specific mortality than HR+HER2+ cases (P = 0.021). In high-risk DCIS cases, RT reduces the absolute 5-year IBE incidence by 1.3%, 0.7%, 1.9%, and 2.6%, respectively in HR-HER2-, HR-HER2+, HR+HER2+, and HR+HER2- cases, respectively. CONCLUSION: In this population-based study, DCIS cases have diverse clinical and prognostic features for different molecular subtypes. Adjusting treatment strategies according to DCIS molecular subtypes is worth advancing.
Subject(s)
Breast Neoplasms , Carcinoma, Ductal, Breast , Carcinoma, Intraductal, Noninfiltrating , Biomarkers, Tumor , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Female , Humans , Mastectomy, Segmental , Neoplasm Recurrence, Local , Prognosis , Receptor, ErbB-2/metabolism , Retrospective StudiesABSTRACT
WHAT IS KNOWN AND OBJECTIVE: Compared with other molecular subtypes, hormone receptor-positive breast cancer often shows worse neoadjuvant chemotherapy efficacy. This study aims to explore the relationship between the oestrogen receptor (ER)-related genes carbonic anhydrase 12 (CA12) and trefoil factor 3 (TFF3) and their predictive value of neoadjuvant chemotherapy for breast cancer. METHODS: We investigated the relationships between CA12, TFF3 and ER status and their predictive value of anthracycline-taxane neoadjuvant chemotherapy in 115 female breast cancer patients via real-time polymerase chain reaction (RT-PCR) and 4 GEO datasets: GSE41998, GSE25065, GSE20194 and GSE20271. Then, the effects of CA12 and TFF3 on the chemotherapy drugs doxorubicin and docetaxel were verified in vitro in the breast cancer cell lines MCF-7 and BT474. RESULTS AND DISCUSSION: The GEO datasets and RT-PCR results showed that the relative expression of both CA12 and TFF3 was higher in oestrogen receptor-positive samples compared with the other samples (p < 0.05). CA12 was significantly correlated with TFF3 (p < 0.05). In MCF-7 cells, inhibition of TFF3 induced downregulation of CA12 and ESR1 (p < 0.05) at both the mRNA and the protein levels, while inhibition of CA12 also downregulated TFF3 and ESR1 (p < 0.05). In BT474 cells, inhibition of TFF3 downregulated CA12 and ESR1 (p < 0.05) at both the mRNA and the protein levels, while inhibition of CA12 led to slight upregulation of TFF3 and ESR1 (p > 0.05). Moreover, GEO datasets and RT-PCR results showed that CA12 and TFF3 were more highly expressed in nonpathological complete response (non-pCR) samples than in pCR samples (p < 0.05). Cell viability assays of MCF-7 and BT474 cells showed that inhibiting CA12 and TFF3 could enhance sensitivity to doxorubicin and docetaxel (p < 0.05). WHAT IS NEW AND CONCLUSION: CA12 and TFF3 were correlated with each other, and their high expression might explain the worse efficacy of neoadjuvant chemotherapy in oestrogen receptor-positive breast cancer patients.
Subject(s)
Breast Neoplasms , Neoadjuvant Therapy , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carbonic Anhydrases , Docetaxel/pharmacology , Doxorubicin/therapeutic use , Female , Humans , RNA, Messenger , Receptors, Estrogen/metabolism , Receptors, Estrogen/therapeutic use , Trefoil Factor-3/geneticsABSTRACT
AIMS: The aim of this study was to analyse the clinicopathological features and prognosis of human epidermal growth factor receptor-2 (HER2)-positive metaplastic squamous cell carcinoma (MSCC). METHODS: Fifty-eight patients with MSCC of the breast who were classified into 45 triple-negative and 13 HER2-positive subgroups diagnosed at the West China Hospital, Sichuan University, from 2004 to 2018, were enrolled. Clinicopathological features were collected and compared between HER2-positive MSCC, triple-negative MSCC, HER2-positive invasive breast carcinoma of no special type (NST) and triple-negative NST groups. In the prognostic survival analysis, HER2-positive MSCCs was compared with triple-negative MSCCs, HER2-positive NSTs and triple-negative NSTs. RESULTS: Compared with triple-negative MSCCs, more patients with Ki-67 low expression were in HER2-positive MSCCs (p<0.05). More patients with HER2-positive MSCC than patients with HER2-positive NST were postmenopausal (p<0.05). Compared among HER2-positive MSCCs, triple-negative MSCCs and triple-negative NSTs, patients of HER2-positive MSCCs with high Ki-67 expression were the least, and HER2-positive MSCCs had more strongly associated with postmenopausal disease status (p<0.05). In survival analyses, HER2-positive MSCCs had a high risk of recurrence and poor prognosis (p<0.05). Lymph node status was significantly associated with the disease-free survival of patients with HER2-positive MSCC. CONCLUSION: In conclusion, our study indicates that HER2-positive MSCC is an aggressive disease with unique clinicopathological characteristics. Both HER2-positive status and an SCC component are critical factors for poor prognosis. HER2-positive MSCC and triple-negative MSCC are distinct subgroups. Corresponding targeted therapy recommendations should be made for this HER2-positive MSCC group.
Subject(s)
Breast Neoplasms/pathology , Carcinoma, Squamous Cell/pathology , Receptor, ErbB-2/metabolism , Adult , Aged , Breast/pathology , Breast Neoplasms/classification , Breast Neoplasms/diagnosis , Carcinoma, Squamous Cell/classification , Carcinoma, Squamous Cell/diagnosis , China , Disease-Free Survival , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Prognosis , Receptor, ErbB-2/geneticsABSTRACT
Background: Recent research has suggested that cardiac regeneration may have the widely applicable potential of treating heart failure (HF). A comprehensive understanding of the development status of this field is conducive to its development. However, no bibliometric analysis has summarized this field properly. We aimed to analyze cardiac regeneration-related literature over 20 years and provide valuable insights. Methods: Publications were collected from the Web of Science Core Collection (WoSCC). Microsoft Excel, VOSviewer, CiteSpace, and alluvial generator were used to analyze and present the data. Results: The collected 11,700 publications showed an annually increasing trend. The United States and Harvard University were the leading force among all the countries and institutions. The majority of articles were published in Circulation Research, and Circulation was the most co-cited journal. According to co-citation analysis, burst detection and alluvial flow map, cardiomyocyte proliferation, stem cells, such as first-and second-generation, extracellular vesicles especially exosomes, direct cardiac reprogramming, macrophages, microRNAs, and inflammation have become more and more popular recently. Conclusions: Cardiac regeneration remains a research hotspot and develops rapidly. How to modify cardiac regeneration endogenously and exogenously may still be the hotspot in the future and should be discussed more deeply.
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Right ventricular (RV) dysfunction induced type II cardiorenal syndrome (CRS) has a high mortality rate, but little attention has been paid to this disease, and its unique molecular characteristics remain unclear. This study aims to investigate the transcriptomic expression profile in this disease and identify key RNA pairs that regulate related molecular signaling networks. We established an RV dysfunction-induced type II CRS mouse model by pulmonary artery constriction (PAC). PAC mice developed severe RV hypertrophy and fibrosis; renal atrophy and dysfunction with elevated creatinine were subsequently observed. Expression profiles in RV and kidney tissues were obtained by whole transcriptome sequencing, revealing a total of 741 and 86 differentially expressed (DE) mRNAs, 159 and 29 DEmiRNAs and 233 and 104 DEcircRNAs between RV and kidney tissue, respectively. Competing endogenous RNA (ceRNA) networks were established. A significant alteration in proliferative, fibrotic and metabolic pathways was found based on GO and KEGG analyses, and the network revealed key ceRNA pairs, such as novel_circ_002631/miR-181a-5p/Creb1 and novel_circ_002631/miR-33-y/Kpan6. These findings indicate that significantly dysregulated pathways in RV dysfunction induced type II CRS include Ras, PI3K/Akt, cGMP-PKG pathways, and thyroid metabolic pathways. These ceRNA pairs can be considered potential targets for the treatment of type II CRS.
Subject(s)
Cardio-Renal Syndrome/genetics , MicroRNAs/metabolism , RNA, Circular/metabolism , RNA, Messenger/metabolism , Renal Insufficiency/genetics , Ventricular Dysfunction, Right/genetics , Animals , Cardio-Renal Syndrome/metabolism , Disease Models, Animal , Fibrosis , Gene Expression , Gene Expression Profiling , Heart Ventricles/metabolism , Heart Ventricles/pathology , Kidney/metabolism , Kidney/pathology , Mice , Myocardium/pathology , Pulmonary Artery/surgery , Renal Insufficiency/metabolism , Renal Insufficiency/pathology , Ventricular Dysfunction, Right/metabolism , Ventricular Dysfunction, Right/pathologyABSTRACT
BACKGROUND: We aimed to analyze the effects of radiotherapy (RT) on the incidence rate of ipsilateral breast event (IBE) in ductal carcinoma in situ (DCIS) patients with lumpectomy after being stratified by prognostic score. METHODS: We identified DCIS patients who received lumpectomy, from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2015. Cumulative incidence functions for competing risk were used to evaluate the effects of RT on IBE risk over time. Three multivariate regression models (weighted, non-weighted, and Fine-Gray) were applied to compare the IBE risk between the RT and non-RT groups after stratifying patients by prognostic score. RESULTS: Overall, 72,623 DCIS patients were identified from the SEER database and 49,206 (66.8%) patients received RT. During the follow-up period (ranging from 7 to 347 months), the cumulative probability of invasive and in situ IBE was significantly lower in the RT group than in the non-RT group (p < 0.001). After being stratified by prognostic score, the weighted IBE incidence rate increased as the risk level increased (p < 0.050). In multivariate regression models, RT lowered the IBE incidence rate by at least 30% in low-, moderate-, and high-risk DCIS (p < 0.010). In particular, the in situ and invasive IBE incidence rate decreased by over 50% in low-risk DCIS with RT (p < 0.001). CONCLUSIONS: RT is associated with a lowered IBE incidence rate in DCIS patients, regardless of the assigned risk levels for patients. The significant reduction in the IBE incidence rate in low-risk DCIS patients also indicates the potential benefits for recommending RT to such a patient population in clinical practice.
Subject(s)
Breast Neoplasms , Carcinoma, Ductal, Breast , Carcinoma, Intraductal, Noninfiltrating , Breast Neoplasms/radiotherapy , Carcinoma, Ductal, Breast/radiotherapy , Carcinoma, Ductal, Breast/surgery , Carcinoma, Intraductal, Noninfiltrating/radiotherapy , Carcinoma, Intraductal, Noninfiltrating/surgery , Humans , Mastectomy, Segmental , PrognosisABSTRACT
Mediator complex subunit 16 (MED16) is a component of the mediator complex and functions as a coactivator in transcriptional events at almost all RNA polymerase II-dependent genes. In this study, we report that the expression of MED16 is markedly decreased in papillary thyroid cancer (PTC) tumors compared with normal thyroid tissues. In vitro, MED16 overexpression in PTC cells significantly inhibited cell migration, enhanced sodium/iodide symporter expression and iodine uptake, and decreased resistance to radioactive 131I (RAI). Conversely, PTC cells in which MED16 had been further knocked down (MED16KD) exhibited enhanced cell migration, epithelial-mesenchymal transition, and RAI resistance, accompanied by decreased sodium/iodide symporter levels. Moreover, cell signaling through transforming growth factor ß (TGF-ß) was highly activated after the MED16 knockdown. Similar results were obtained in MED12KD PTC cells, and a co-immunoprecipitation experiment verified interactions between MED16 and MED12 and between MED16 and TGF-ßR2. Of note, the application of LY2157299, a potent inhibitor of TGF-ß signaling, significantly attenuated MED16KD-induced RAI resistance both in vitro and in vivo In conclusion, our findings indicate that MED16 reduction in PTC contributes to tumor progression and RAI resistance via the activation of the TGF-ß pathway.
Subject(s)
Iodine Radioisotopes/pharmacology , Mediator Complex/metabolism , Neoplasm Proteins/metabolism , Radiation Tolerance , Signal Transduction , Thyroid Cancer, Papillary , Thyroid Neoplasms , Transforming Growth Factor beta/metabolism , Animals , Cell Line, Tumor , Female , Humans , Mediator Complex/genetics , Mice , Mice, Nude , Neoplasm Proteins/genetics , Radiation Tolerance/drug effects , Radiation Tolerance/radiation effects , Signal Transduction/drug effects , Signal Transduction/radiation effects , Thyroid Cancer, Papillary/metabolism , Thyroid Cancer, Papillary/pathology , Thyroid Cancer, Papillary/radiotherapy , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , Thyroid Neoplasms/radiotherapyABSTRACT
The role of the cardiac isoform of the electrogenic sodium-bicarbonate ion cotransporter (NBCe1) in cardiac remodeling is not fully understood. The aim of this study was to assess the effects of NBCe1 overexpression on cardiac remodeling induced by myocardial infarction (MI) in mice. We generated NBCe1 transgenic (Tg) mice and NBCe1 overexpressing adult mouse ventricular myocytes (AMVMs) to investigate the role of NBCe1 on post-MI remodeling and calcium kinetics. Tg mice showed a markedly higher mortality rate and larger infarct size after MI. At 6 weeks after MI, the maximum rising rates of left ventricular pressure (dp/dt), contractility index, and the exponential time constant of relaxation (τ) were markedly lower, and there was higher cardiomyocyte apoptosis, in Tg mice compared with WT mice. In cultured AMVMs, overexpression of NBCe1 decreased sarcomere shortening and calcium amplitude. In WT AMVMs, the rates of the rise and decay phase of calcium transients, indicated by the rising time (Tpeak, time to peak) and decay time constant (τd), and the number of apoptotic cells, were increased following hypoxia, while overexpression of NBCe1 further increased Tpeak and cellular apoptosis, but not τd. Intracellular resting calcium and sodium concentrations were significantly increased following both hypoxia and NBCe1 overexpression. Co-treatment with S0859, an NBCe1 antagonist, blocked the hypoxia-induced increase in Tpeak, τd, intracellular resting calcium and sodium concentrations, and apoptosis in cardiomyocytes. These findings indicate that NBCe1 overexpression promotes cardiac remodeling by increasing intracellular calcium overload. Therefore, NBCe1 should be a potential target for treatment of cardiac remodeling.