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1.
Foods ; 13(16)2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39200461

RESUMO

In fermented foods, acetic acid bacteria (AAB), kinds of bacteria with a long history of utilization, contribute to safety, nutritional, and sensory properties primarily through acetic acid fermentation. AAB are commonly found in various fermented foods such as vinegar, sour beer, fermented cocoa and coffee beans, kefir beverages, kombucha, and sourdough. They interact and cooperate with a variety of microorganisms, resulting in the formation of diverse metabolites and the production of fermented foods with distinct flavors. Understanding the interactions between AAB and other microbes is crucial for effectively controlling and utilizing AAB in fermentation processes. However, these microbial interactions are influenced by factors such as strain type, nutritional conditions, ecological niches, and fermentation duration. In this review, we examine the relationships and research methodologies of microbial interactions and interaction studies between AAB and yeasts, lactic acid bacteria (LAB), and bacilli in different food fermentation processes involving these microorganisms. The objective of this review is to identify key interaction models involving AAB and other microorganisms. The insights gained will provide scientific guidance for the effective utilization of AAB as functional microorganisms in food fermentation processes.

2.
Environ Pollut ; 357: 124402, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38906405

RESUMO

Excess nitrogen and phosphorus inputs are the main causes of aquatic environmental deterioration. Accurately quantifying and dynamically assessing the regional nitrogen and phosphorus pollution emission (NPPE) loads and influencing factors is crucial for local authorities to implement and formulate refined pollution reduction management strategies. In this study, we constructed a methodological framework for evaluating the spatio-temporal evolution mechanism and dynamic simulation of NPPE. We investigated the spatio-temporal evolution mechanism and influencing factors of NPPE in the Yangtze River Economic Belt (YREB) of China through the pollution load accounting model, spatial correlation analysis model, geographical detector model, back propagation neural network model, and trend analysis model. The results show that the NPPE inputs in the YREB exhibit a general trend of first rising and then falling, with uneven development among various cities in each province. Nonpoint sources are the largest source of land-based NPPE. Overall, positive spatial clustering of NPPE is observed in the cities of the YREB, and there is a certain enhancement in clustering. The GDP of the primary industry and cultivated area are important human activity factors affecting the spatial distribution of NPPE, with economic factors exerting the greatest influence on the NPPE. In the future, the change in NPPE in the YREB at the provincial level is slight, while the nitrogen pollution emissions at the municipal level will develop towards a polarization trend. Most cities in the middle and lower reaches of the YREB in 2035 will exhibit medium to high emissions. This study provides a scientific basis for the control of regional NPPE, and it is necessary to strengthen cooperation and coordination among cities in the future, jointly improve the nitrogen and phosphorus pollution tracing and control management system, and achieve regional sustainable development.


Assuntos
Monitoramento Ambiental , Nitrogênio , Fósforo , Rios , Análise Espaço-Temporal , Poluentes Químicos da Água , Fósforo/análise , China , Nitrogênio/análise , Rios/química , Poluentes Químicos da Água/análise , Poluição Química da Água/estatística & dados numéricos
3.
Front Microbiol ; 15: 1389737, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38756727

RESUMO

Introduction: The starter used in solid-state fermentation (SSF) vinegar, known as seed Pei is a microbial inoculant from the previous batch that is utilized during the acetic acid fermentation stage. The seed Pei, which has a notable impact on vinegar fermentation and flavor, is under-researched with comparative studies on microorganisms. Methods: Herein metagenomics was employed to reveal the microbes and their potential metabolic functions of four seed Pei from three regions in China. Results: The predominant microbial taxa in all four starters were bacteria, followed by viruses, eukaryotes, and archaea, with Lactobacillus sp. or Acetobacter sp. as main functional taxa. The seed Pei used in Shanxi aged vinegar (SAV) and Sichuan bran vinegar (SBV) exhibited a higher similarity in microbial composition and distribution of functional genes, while those used in two Zhenjiang aromatic vinegar (ZAV) differed significantly. Redundancy analysis (RDA) of physicochemical factors and microbial communities indicated that moisture content, pH, and reducing sugar content are significant factors influencing microbial distribution. Moreover, seven metagenome-assembled genomes (MAGs) that could potentially represent novel species were identified. Conclusions: There are distinctions in the microbiome and functional genes among different seed Pei. The vinegar starters were rich in genes related to carbohydrate metabolism. This research provides a new perspective on formulating vinegar fermentation starters and developing commercial fermentation agents for vinegar production.

4.
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
5.
Cancer Res ; 83(10): 1711-1724, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37129951

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with unfavorable outcomes. Developing therapeutic targets for TNBC remains a challenge. Here, we identified that acetyl-CoA acyltransferase 1 (ACAA1) is highly expressed in the luminal androgen receptor (LAR) subtype of TNBC compared with adjacent normal tissues in our TNBC proteomics dataset. Inhibition of ACAA1 restrained TNBC proliferation and potentiated the response to the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib. Mechanistically, ACAA1 interacted with CDK4, and the inhibition of ACAA1 blocked RB transcriptional corepressor 1 (RB1) phosphorylation, resulting in G1-S cell-cycle arrest. Importantly, trimetazidine, a traditional drug for ischemic heart disease, caused a decrease in ACAA1 protein levels and enhanced the efficacy of abemaciclib in preclinical TNBC models. In conclusion, this study identifies that ACAA1 is a therapeutic target in TNBC and suggests the combination of trimetazidine and abemaciclib could be beneficial for ACAA1-high TNBCs. SIGNIFICANCE: ACAA1 is highly expressed in TNBC, serving as a potential therapeutic target in ACAA1-high tumors and a predictive biomarker of resistance to CDK4/6 inhibitors for RB1-proficient patients.


Assuntos
Trimetazidina , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Trimetazidina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinase 4 Dependente de Ciclina , Acetil-CoA C-Aciltransferase
6.
Proc Natl Acad Sci U S A ; 119(46): e2207201119, 2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36343244

RESUMO

The transcription variation, leading to various forms of transcripts and protein diversity, remains largely unexplored in triple-negative breast cancers (TNBCs). Here, we presented a comprehensive analysis of RNA splicing in breast cancer to illustrate the biological function and clinical implications of tumor-specific transcripts (TSTs) arising from these splicing junctions. Aberrant RNA splicing or TSTs were frequently harbored in TNBC and were correlated with a poor outcome. We discovered a tumor-specific splicing variant of macrophage receptor with collagenous structure-TST (MARCO-TST), which was distinguished from myeloid cell-specific wild-type MARCO. MARCO-TST expression was associated with poor outcomes in TNBC patients and could promote tumor progression in vitro and in vivo. Mechanically, MARCO-TST interacted with PLOD2 and enhanced the stability of HIF-1α, which resulted in the metabolic dysregulation of TNBC to form a hypoxic tumor microenvironment. MARCO-TST was initiated from a de novo alternative transcription initiation site that was activated by a superenhancer. Tumors with MARCO-TST expression conferred greater sensitivity to bromodomain and extraterminal protein inhibitors. This treatment strategy was further validated in patient-derived organoids. In conclusion, our results revealed the transcription variation landscape of TNBC, highlighting MARCO-TST as a crucial oncogenic transcript and therapeutic target.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Carcinogênese/genética , Splicing de RNA , Proliferação de Células , Microambiente Tumoral
7.
Clin Transl Med ; 12(5): e825, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35522895

RESUMO

AIMS: MORC family CW-type zinc finger 2 (MORC2), a GHKL-type ATPase, is aberrantly upregulated in multiple types of human tumors with profound effects on cancer aggressiveness, therapeutic resistance, and clinical outcome, thus making it an attractive drug target for anticancer therapy. However, the antagonists of MORC2 have not yet been documented. METHODS AND RESULTS: We report that MORC2 is a relatively stable protein, and the N-terminal homodimerization but not ATP binding and hydrolysis is crucial for its stability through immunoblotting analysis and Quantitative real-time PCR. The N-terminal but not C-terminal inhibitors of heat shock protein 90 (HSP90) destabilize MORC2 in multiple cancer cell lines, and strikingly, this process is independent on HSP90. Mechanistical investigations revealed that HSP90 N-terminal inhibitors disrupt MORC2 homodimer formation without affecting its ATPase activities, and promote its lysosomal degradation through the chaperone-mediated autophagy pathway. Consequently, HSP90 inhibitor 17-AAG effectively blocks the growth and metastatic potential of MORC2-expressing breast cancer cells both in vitro and in vivo, and these noted effects are not due to HSP90 inhibition. CONCLUSION: We uncover a previously unknown role for HSP90 N-terminal inhibitors in promoting MORC2 degradation in a HSP90-indepentent manner and support the potential application of these inhibitors for treating MORC2-overexpressing tumors, even those with low or absent HSP90 expression. These results also provide new clue for further design of novel small-molecule inhibitors of MORC2 for anticancer therapeutic application.


Assuntos
Antineoplásicos , Neoplasias da Mama , Fatores de Transcrição , Adenosina Trifosfatases/genética , Antineoplásicos/farmacologia , Autofagia/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Humanos , Proteínas Oncogênicas
8.
Breast Cancer Res Treat ; 193(2): 319-330, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35334008

RESUMO

PURPOSE: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Patients with early-stage TNBCs have distinct likelihood of distant recurrence. This study aimed to develop a prognostic signature of early-stage TNBC patients to improve risk stratification. METHODS: Using RNA-sequencing data, we analyzed 189 pathologically confirmed pT1-2N0M0 TNBC patients and identified 21 mRNAs that were highly expressed in tumor and related to relapse-free survival. All-subset regression program was used for constructing a 7-mRNA signature in the training set (n = 159); the accuracy and prognostic value were then validated using an independent validation set (n = 158). RESULTS: Here, we profiled the transcriptome data from 189 early-stage TNBC patients along with 50 paired normal tissues. Early-stage TNBCs mainly consisted of basal-like immune-suppressed subtype and had higher homologous recombination deficiency scores. We developed a prognostic signature including seven mRNAs (ACAN, KRT5, TMEM101, LCA5, RPP40, LAGE3, CDKL2). In both the training (n = 159) and validation set (n = 158), this signature could identify patients with relatively high recurrence risks and served as an independent prognostic factor. Time-dependent receiver operating curve showed that the signature had better prognostic value than traditional clinicopathological features in both sets. Functionally, we showed that TMEM101 promoted cell proliferation and migration in vitro, which represented a potential therapeutic target. CONCLUSIONS: Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. This model may facilitate personalized therapy decision-making for early-stage TNBCs individuals.


Assuntos
Biomarcadores Tumorais , Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , RNA Mensageiro/genética , Transcriptoma , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/terapia
9.
Cell Res ; 32(5): 477-490, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35105939

RESUMO

Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Humanos , Metabolômica , Medicina de Precisão , Transcriptoma , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
10.
Clin Transl Med ; 11(11): e589, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34842356

RESUMO

BACKGROUND: Few studies have discussed the contradictory roles of mutated-PI3Kα in HER2-positive (HER2+) breast cancer. Thus, we characterised the adaptive roles of PI3Kα mutations among HER2+ tumour progression. METHODS: We conducted prospective clinical sequencing of 1923 Chinese breast cancer patients and illustrated the clinical significance of PIK3CA mutations in locally advanced and advanced HER2+ cohort. A high-throughput PIK3CA mutations-barcoding screen was performed to reveal impactful mutation sites in tumour growth and drug responses. RESULTS: PIK3CA mutations acted as a protective factor in treatment-naïve patients; however, advanced/locally advanced patients harbouring mutated-PI3Kα exhibited a higher progressive disease rate (100% vs. 15%, p = .000053) and a lower objective response rate (81.7% vs. 95.4%, p = .0008) in response to trastuzumab-based therapy. Meanwhile, patients exhibiting anti-HER2 resistance had a relatively high variant allele fraction (VAF) of PIK3CA mutations; we defined the VAF > 12.23% as a predictor of poor anti-HER2 neoadjuvant treatment efficacy. Pooled mutations screen revealed that specific PI3Kα mutation alleles mediated own biological effects. PIK3CA functional mutations suppressed the growth of HER2+ cells, but conferred anti-HER2 resistance, which can be reversed by the PI3Kα-specific inhibitor BYL719. CONCLUSIONS: We proposed adaptive treatment strategies that the mutated PIK3CA and amplified ERBB2 should be concomitantly inhibited when exposing to continuous anti-HER2 therapy, while the combination of anti-HER2 and anti-PI3Kα treatment was not essential for anti-HER2 treatment-naïve patients. These findings improve the understanding of genomics-guided treatment in the different progressions of HER2+ breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/genética , Análise de Sequência/estatística & dados numéricos , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Fisiológica/genética , Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , China , Estudos de Coortes , Feminino , Humanos , Estudos Prospectivos , Análise de Sequência/métodos
11.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34281987

RESUMO

PURPOSE: Regulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC. EXPERIMENTAL DESIGN: Using the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism. RESULTS: We revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy. CONCLUSIONS: Tumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.


Assuntos
GTP Cicloidrolase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Linfócitos T Reguladores/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Animais , Feminino , Humanos , Camundongos , Regulação para Cima
12.
Oncogene ; 40(12): 2323-2334, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33654196

RESUMO

Progression of triple-negative breast cancer (TNBC) constitutes a major unresolved clinical challenge, and effective targeted therapies are lacking. Because microtubule dynamics play pivotal roles in breast cancer metastasis, we performed RNA sequencing on 245 samples from TNBC patients to characterize the landscape of microtubule-associated proteins (MAPs). Here, our transcriptome analyses revealed that low expression of one MAP, tektin4, indicated poor patient outcomes. Tektin4 loss led to a marked increase in TNBC migration, invasion, and metastasis and a decrease in microtubule stability. Mechanistically, we identified a novel microtubule-associated complex containing tektin4 and histone deacetylase 6 (HDAC6). Tektin4 loss increased the interaction between HDAC6 and α-tubulin, thus decreasing microtubule stability through HDAC6-mediated tubulin deacetylation. Significantly, we found that tektin4 loss sensitized TNBC cells, xenograft models, and patient-derived organoid models to the HDAC6-selective inhibitor ACY1215. Furthermore, tektin4 expression levels were positively correlated with microtubule stability levels in clinical samples. Together, our findings uncover a metastasis suppressor function of tektin4 and support clinical development of HDAC6 inhibition as a new therapeutic strategy for tektin4-deficient TNBC patients.


Assuntos
Desacetilase 6 de Histona/genética , Inibidores de Histona Desacetilases/farmacologia , Proteínas dos Microtúbulos/genética , Neoplasias de Mama Triplo Negativas/genética , Tubulina (Proteína)/genética , Acetilação/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Ácidos Hidroxâmicos/farmacologia , Camundongos , Metástase Neoplásica , Pirimidinas/farmacologia , Análise de Sequência de RNA , Neoplasias de Mama Triplo Negativas/patologia , Sequenciamento do Exoma
13.
Cell Metab ; 33(1): 51-64.e9, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33181091

RESUMO

Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of lactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.


Assuntos
Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Feminino , Humanos , Imunoterapia , Masculino , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/terapia , Células Tumorais Cultivadas
14.
Nat Commun ; 11(1): 5679, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173047

RESUMO

The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.


Assuntos
Povo Asiático/genética , Neoplasias da Mama , Terapia de Alvo Molecular , Mutação , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , China , Gerenciamento de Dados , Feminino , Marcadores Genéticos , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neurofibromina 2/genética , Oncogenes , Medicina de Precisão , Estudos Prospectivos , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética
15.
Theranostics ; 10(24): 10940-10956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042263

RESUMO

Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance. Methods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms. Results: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization. Conclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Recidiva Local de Neoplasia/epidemiologia , Paclitaxel/farmacologia , Neoplasias de Mama Triplo Negativas/terapia , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Animais , Mama/patologia , Mama/cirurgia , Linhagem Celular Tumoral , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Microscopia Intravital , Mastectomia , Camundongos , Microtúbulos/metabolismo , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/genética , Organoides , Paclitaxel/uso terapêutico , Prognóstico , Multimerização Proteica/genética , RNA-Seq , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Tubulina (Proteína)/metabolismo , Células Tumorais Cultivadas , Proteínas de Transporte Vesicular/metabolismo , Adulto Jovem
16.
Cancer Cell ; 35(3): 428-440.e5, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30853353

RESUMO

We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Receptor ErbB-2/genética , Neoplasias de Mama Triplo Negativas/classificação , Povo Asiático/genética , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 22/genética , Variações do Número de Cópias de DNA , Feminino , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Metástase Neoplásica , Prognóstico , Neoplasias de Mama Triplo Negativas/genética
17.
Transl Cancer Res ; 8(2): 614-625, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35116794

RESUMO

BACKGROUND: Whether primary tumor surgery should be performed in breast cancer patients with metastatic disease at diagnosis has been debated for decades. This study aims to evaluate the value of primary tumor surgery with respect to the mortality of patients with de novo stage IV breast cancer and to define the heterogeneity of this population. METHODS: De novo stage IV patients from the Surveillance, Epidemiology and End Results database (SEER) from 2010 to 2015 were included in our study. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to achieve balanced baseline characteristics. The effect of surgery was assessed by Kaplan-Meier curves and Cox regression models. RESULTS: Of the 11,684 patients eligible for analysis, 3,730 (31.92%) received primary tumor surgery. Multivariate Cox regression in the PSM cohort revealed that surgery was associated with better outcomes than those in the nonsurgery group in terms of overall survival (OS) [hazard ratio (HR): 0.51; 95% CI: 0.48-0.55; P<0.001] and breast cancer-specific survival (BCSS) (HR: 0.51; 95% CI: 0.47-0.55; P<0.001). IPTW analysis yielded similar results. In a subgroup analysis, surgery was associated with better survival in all subtypes with low metastatic burdens (≤2 metastatic sites), but triple-negative breast cancer with a high metastatic burden (>2 metastatic sites) did not benefit from surgery (HR: 0.78; 95% CI: 0.31-1.97, P=0.596 and 0.78, 95% CI: 0.31-1.97, P=0.596 for OS and BCSS, respectively). CONCLUSIONS: Primary tumor surgery significantly prolonged the survival of patients with de novo stage IV breast cancer. However, triple-negative breast cancer patients with more than two metastatic sites may not benefit from surgery.

18.
J Vasc Surg Venous Lymphat Disord ; 6(5): 636-645, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29784593

RESUMO

OBJECTIVE: We aimed to review our experience in the diagnosis and surgical management of patients diagnosed with inferior vena cava leiomyomatosis (IVL). METHODS: We retrospectively evaluated all patients diagnosed with IVL between 1999 and 2015. Patient demographics, diagnostic imaging, operative techniques, and perioperative outcomes were reviewed. RESULTS: Over the study period, 16 patients with an IVL diagnosis were identified. In all patients, the diagnosis was made with ultrasound and magnetic resonance imaging. In 15 patients who underwent operative intervention, we observed three tumor extension routes from the uterus to the inferior vena cava: (i) via the internal iliac vein, (ii) via the ovarian vein, and (iii) via the anterior sacral vein. Complete tumor removal was achieved in all patients who underwent a one-stage operation (12 patients). Among these patients, antegrade tumor extraction from the right atrium was performed in nine patients, and retrograde extraction from iliac veins was performed in three. A two-stage operation with direct tumor transection and resection was necessary in a subset of patients to facilitate complete resection in one patient, and near-complete resection in two patients. Preoperative imaging and intraoperative findings demonstrated four distinct types of gross tumor morphologies: (i) type A solid cast (43.8%), (ii) type B hallow tube-like (12.5%), (iii) type C thread-like (18.7%), and (iv) type D mixed morphology (25%). Types A and B were the easiest tumor types to extract, and types C and D tumors were more difficult to remove given their fragility. Postoperative surgical pathology confirmed the diagnosis of IVL. All patients recovered successfully with no major complications; there were no deaths. One patient early in our experience had an incomplete resection and developed a recurrence that required re-intervention at 26 months from the initial operation. CONCLUSIONS: IVL can be accurately diagnosed with ultrasound and magnetic resonance imaging. Surgical tumor resection with a one-stage operation can lead to reasonable outcomes and successful cure rates. The surgical plan can be tailored to the type of tumor morphology observed on preoperative imaging.


Assuntos
Leiomiomatose/diagnóstico por imagem , Leiomiomatose/cirurgia , Neoplasias Vasculares/diagnóstico por imagem , Neoplasias Vasculares/cirurgia , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Inferior/cirurgia , Adulto , Ecocardiografia Doppler , Feminino , Seguimentos , Átrios do Coração/patologia , Átrios do Coração/cirurgia , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/cirurgia , Humanos , Leiomiomatose/patologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Complicações Pós-Operatórias , Estudos Retrospectivos , Ultrassonografia , Neoplasias Uterinas/patologia , Neoplasias Vasculares/patologia , Veia Cava Inferior/patologia
19.
J Vasc Surg Venous Lymphat Disord ; 5(2): 254-256, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28214494

RESUMO

Intravenous leiomyomatosis is a benign smooth muscle tumor that often occurs in the internal iliac vein and is closely associated with a fibroid. Intravenous leiomyomatosis usually starts in the veins of the uterus. It can grow within the veins and extend into the inferior vena cava and ultimately extend into the right-sided heart chambers and pulmonary arteries. Other sites are less common, and a venous primary site is very rare. We report a case of subclavian vein tumor that was diagnosed as an unusual leiomyoma in a 21-year-old nulliparous woman.


Assuntos
Leiomiomatose/diagnóstico , Neoplasias Musculares/diagnóstico , Veia Subclávia , Neoplasias Vasculares/diagnóstico , Humanos , Leiomiomatose/cirurgia , Angiografia por Ressonância Magnética , Masculino , Imagem Multimodal , Neoplasias Musculares/cirurgia , Músculo Liso Vascular , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ultrassonografia Doppler em Cores , Neoplasias Vasculares/cirurgia , Adulto Jovem
20.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 37(1): 106-108, 2017 01.
Artigo em Chinês | MEDLINE | ID: mdl-30695434

RESUMO

Objective In this paper the author summarized the contents of clinical research of Chinese medicine ( CM) and Western medicine (WM) from thinking methods based on literature re- search. He believed there were two kinds of main contents: (1) Combine CM syndrome typing and WM disease identification based on clinical experiences; (2) Limit the flexibility of CM syndrome typing within recognition of WM depending on modern scientific researches, thus realizing the integration of macrosyndrome typing and micro-disease identification. Based on these contents, the author expounded future development of CM and WM from future goals, tasks, feasible ways, and specific work.


Assuntos
Medicina Integrativa , Humanos , Medicina Tradicional Chinesa , Síndrome
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