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1.
Proc Natl Acad Sci U S A ; 121(7): e2307150121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38315842

RESUMO

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcription initiation and is essential for maintaining gene silencing at heterochromatic loci. Inhibition of CDK9 increases sensitivity to immunotherapy, but the underlying mechanism remains unclear. We now report that RNF20 stabilizes LSD1 via K29-mediated ubiquitination, which is dependent on CDK9-mediated phosphorylation. This CDK9- and RNF20-dependent LSD1 stabilization is necessary for the demethylation of histone H3K4, then subsequent repression of endogenous retrovirus, and an interferon response, leading to epigenetic immunosuppression. Moreover, we found that loss of RNF20 sensitizes cancer cells to the immune checkpoint inhibitor anti-PD-1 in vivo and that this effect can be rescued by the expression of ectopic LSD1. Our findings are supported by the observation that RNF20 levels correlate with LSD1 levels in human breast cancer specimens. This study sheds light on the role of RNF20 in CDK9-dependent LSD1 stabilization, which is crucial for epigenetic silencing and immunosuppression. Our findings explore the potential importance of targeting the CDK9-RNF20-LSD1 axis in the development of new cancer therapies.


Assuntos
Quinase 9 Dependente de Ciclina , Histona Desmetilases , Tolerância Imunológica , Ubiquitina-Proteína Ligases , Humanos , Quinase 9 Dependente de Ciclina/genética , Quinase 9 Dependente de Ciclina/metabolismo , Epigênese Genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Ubiquitina-Proteína Ligases/genética
2.
Chem Rev ; 123(15): 9676-9717, 2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37428987

RESUMO

Multicomponent metallic nanomaterials with unconventional phases show great prospects in electrochemical energy storage and conversion, owing to unique crystal structures and abundant structural effects. In this review, we emphasize the progress in the strain and surface engineering of these novel nanomaterials. We start with a brief introduction of the structural configurations of these materials, based on the interaction types between the components. Next, the fundamentals of strain, strain effect in relevant metallic nanomaterials with unconventional phases, and their formation mechanisms are discussed. Then the progress in surface engineering of these multicomponent metallic nanomaterials is demonstrated from the aspects of morphology control, crystallinity control, surface modification, and surface reconstruction. Moreover, the applications of the strain- and surface-engineered unconventional nanomaterials mainly in electrocatalysis are also introduced, where in addition to the catalytic performance, the structure-performance correlations are highlighted. Finally, the challenges and opportunities in this promising field are prospected.

3.
Proc Natl Acad Sci U S A ; 119(28): e2119518119, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35867755

RESUMO

Early B cell factor 1 (EBF1) is a transcriptional factor with a variety of roles in cell differentiation and metabolism. However, the functional roles of EBF1 in tumorigenesis remain elusive. Here, we demonstrate that EBF1 is highly expressed in triple-negative breast cancer (TNBC). Furthermore, EBF1 has a pivotal role in the tumorigenicity and progression of TNBC. Moreover, we found that depletion of EBF1 induces extensive cell mitophagy and inhibits tumor growth. Genome-wide mapping of the EBF1 transcriptional regulatory network revealed that EBF1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that fine-tunes the expression of HIF1α targets via suppression of p300 activity. EBF1 therefore holds HIF1α activity in check to avert extensive mitophagy-induced cell death. Our findings reveal a key function for EBF1 as a master regulator of mitochondria homeostasis in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Transativadores , Neoplasias de Mama Triplo Negativas , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
4.
Nano Lett ; 24(4): 1205-1213, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38214250

RESUMO

Amorphous nanomaterials have drawn extensive attention owing to their unique features, while amorphization on noble metal nanomaterials still remains formidably challenging. Herein, we demonstrate a universal strategy to synthesize amorphous Pd-based nanomaterials from unary to quinary metals through the introduction of phosphorus (P). The amorphous Pd-based nanoparticles (NPs) exhibit generally promoted oxygen reduction reaction (ORR) activity and durability compared with their crystalline counterparts. Significantly, the quinary P-PdCuNiInSn NPs, benefiting from the amorphous structure and multimetallic component effect, exhibit mass activities as high as 1.04 A mgPd-1 and negligible activity decays of 1.8% among the stability tests, which are much better than values for original Pd NPs (0.134 A mgPd-1 and 28.4%). Experimental and theoretical analyses collectively reveal that the synergy of P-induced amorphization and the expansion of metallic components can considerably lower the free energy changes in the rate-determined step, thereby explaining the positive correlation with the catalytic activity.

5.
BMC Cancer ; 24(1): 13, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38166846

RESUMO

PURPOSE: The residual cancer burden index (RCB) was proposed as a response evaluation criterion in breast cancer patients treated with Neoadjuvant Chemotherapy (NAC). This study evaluated the relevance of RCB with replase-free survival (RFS). METHODS: The clinical data of 254 breast cancer patients who received NAC between 2016 and 2020 were retrospectively collected. The relationship between clinicopathologic factors and RFS was evaluated using Cox proportional hazards regression models. RFS estimates were determined by Kaplan-Meier(K-M) analysis and compared using the log-rank test. Multivariate logistic regression analysis was used to evaluate the risk factors associated with RCB. Receiver operating characteristic (ROC) curves showed the potential of the RCB and MP grading systems as biomarkers for RFS. RESULTS: At a median follow-up of 52 months, 59 patients(23.23%) developed relapse. Multivariate Cox regression showed that older age (P = 0.022), high Pathologic T stage after NAC (P = 0.023) and a high RCB score(P = 0.003) were risk factors for relapse. The outcomes of the multivariate logistic analysis indicated that RCB 0 (pathologic complete response [pCR]) was associated with HER2-positive patients (P = 0.002) and triple-negative breast cancer (TNBC) patients (P = 0.013). In addition, the RCB and MP scoring systems served as prognostic markers for patients who received NAC, and their area under curves (AUCs) were 0.691 and 0.342, respectively. CONCLUSION: These data suggest that RCB can be equally applied to predict RFS in Chinese patients with NAC. The application of RCB may help guide the selection of treatment strategies.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/patologia , Prognóstico , Terapia Neoadjuvante , Neoplasia Residual/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Recidiva , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
6.
Nature ; 561(7722): 189-194, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30209367

RESUMO

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins-a class of natural products with weak activity and limited spectrum-to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.


Assuntos
Antibacterianos/classificação , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Biocatálise/efeitos dos fármacos , Produtos Biológicos/classificação , Produtos Biológicos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/enzimologia , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Negativas/patogenicidade , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/patogenicidade , Lisina/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/química , Porinas , Ligação Proteica , Domínios Proteicos , Serina Endopeptidases , Especificidade por Substrato
7.
Mikrochim Acta ; 191(6): 325, 2024 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-38739279

RESUMO

Glial fibrillary acidic protein (GFAP) in serum has been shown as a biomarker of traumatic brain injury (TBI) which is a significant global public health concern. Accurate and rapid detection of serum GFAP is critical for TBI diagnosis. In this study, a time-resolved fluorescence immunochromatographic test strip (TRFIS) was proposed for the quantitative detection of serum GFAP. This TRFIS possessed excellent linearity ranging from 0.05 to 2.5 ng/mL for the detection of serum GFAP and displayed good linearity (Y = 598723X + 797198, R2 = 0.99), with the lowest detection limit of 16 pg/mL. This TRFIS allowed for quantitative detection of serum GFAP within 15 min and showed high specificity. The intra-batch coefficient of variation (CV) and the inter-batch CV were both < 4.0%. Additionally, this TRFIS was applied to detect GFAP in the serum samples from healthy donors and patients with cerebral hemorrhage, and the results of TRFIS could efficiently discern the patients with cerebral hemorrhage from the healthy donors. Our developed TRFIS has the characteristics of high sensitivity, high accuracy, and a wide linear range and is suitable for rapid and quantitative determination of serum GFAP on-site.


Assuntos
Cromatografia de Afinidade , Proteína Glial Fibrilar Ácida , Humanos , Biomarcadores/sangue , Hemorragia Cerebral/sangue , Hemorragia Cerebral/diagnóstico , Cromatografia de Afinidade/métodos , Proteína Glial Fibrilar Ácida/sangue , Limite de Detecção , Fitas Reagentes
8.
Mikrochim Acta ; 191(6): 311, 2024 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-38717575

RESUMO

Urine retinol-binding protein 4 (RBP4) has recently been reported as a novel earlier biomarker of chronic kidney disease (CKD) which is a global public health problem with high morbidity and mortality. Accurate and rapid detection of urine RBP4 is essential for early monitor of impaired kidney function and prevention of CKD progression. In the present study, we developed a time-resolved fluorescence immunochromatographic test strip (TRFIS) for the quantitative and rapid detection of urine RBP4. This TRFIS possessed excellent linearity ranging from 0.024 to 12.50 ng/mL for the detection of urine RBP4, and displayed a good linearity (Y = 239,581 × X + 617,238, R2 = 0.9902), with the lowest visual detection limit of 0.049 ng/mL. This TRFIS allows for quantitative detection of urine RBP4 within 15 min and shows high specificity. The intra-batch coefficient of variation (CV) and the inter-batch CV were both < 8%, respectively. Additionally, this TRFIS was applied to detect RBP4 in the urine samples from healthy donors and patients with CKD, and the results of TRFIS could efficiently discern the patients with CKD from the healthy donors. The developed TRFIS has the characteristics of high sensitivity, high accuracy, and a wide linear range, and is suitable for rapid and quantitative determination of urine RBP4.


Assuntos
Cromatografia de Afinidade , Insuficiência Renal Crônica , Proteínas Plasmáticas de Ligação ao Retinol , Humanos , Proteínas Plasmáticas de Ligação ao Retinol/urina , Cromatografia de Afinidade/métodos , Insuficiência Renal Crônica/urina , Insuficiência Renal Crônica/diagnóstico , Limite de Detecção , Fitas Reagentes , Biomarcadores/urina , Imunoensaio/métodos
9.
Int J Cancer ; 153(10): 1809-1818, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37543965

RESUMO

Pyrotinib, an irreversible pan-ErbB inhibitor, has been approved for treating HER2-positive advanced breast cancer in China. We conducted a nationwide, prospective observational study to examine the real-world data of pyrotinib-based therapy in this population. Patients from 61 sites across China were included. Pyrotinib-based regimens were prescribed at local physician's discretion. Demographics, treatment patterns, prognosis and safety were evaluated. The primary outcome was real-world progression-free survival (rwPFS). Of 1129 patients, pyrotinib-based therapy was prescribed as first-, second- and third- or later-line treatment in 437 (38.7%), 476 (42.2%) and 216 (19.1%) patients, respectively. Median rwPFS (mrwPFS) was 14.3 (95% CI, 13.3-15.2) months in the total population, with the longest mrwPFS of 17.8 (95% CI, 15.2-24.9) months in the first-line setting, followed by 14.4 (95% CI, 12.9-15.3) months in the second-line setting. Patients with third- or later-line treatment also achieved a mrwPFS of 9.3 (95% CI, 8.4-11.8) months. Patients with trastuzumab- or trastuzumab-pertuzumab-treated disease achieved a mrwPFS of 14.3 and 13.6 months, respectively. Dual HER2 blockade with pyrotinib plus trastuzumab showed a mrwPFS of 16.2 months in the total population, with data not mature in the first-line setting. For patients with baseline brain metastases, the mrwPFS was 11.7 months. The most common adverse event was diarrhea (any grade, 73.5%; grade ≥ 3, 15.3%). In real world, pyrotinib-based therapy shows promising effectiveness in the first-, as well as second- and later-line treatment, with acceptable tolerability. Further investigations regarding front-line use or novel combinations of pyrotinib might facilitate to maximize its anti-tumor potential.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Receptor ErbB-2 , Estudos Prospectivos , Trastuzumab/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica
10.
BMC Med ; 21(1): 493, 2023 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-38087296

RESUMO

BACKGROUND: The pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) of breast cancer is closely related to a better prognosis. However, there are no reliable indicators to accurately identify which patients will achieve pCR before surgery, and a model for predicting pCR to NAC is required. METHODS: A total of 269 breast cancer patients in Shandong Cancer Hospital and Liaocheng People's Hospital receiving anthracycline and taxane-based NAC were prospectively enrolled. Expression profiling using a 457 cancer-related gene sequencing panel (DNA sequencing) covering genes recurrently mutated in breast cancer was carried out on 243 formalin-fixed paraffin-embedded tumor biopsies samples before NAC from 243 patients. The unique personalized panel of nine individual somatic mutation genes from the constructed model was used to detect and analyze ctDNA on 216 blood samples. Blood samples were collected at indicated time points including before chemotherapy initiation, after the 1st NAC and before the 2nd NAC cycle, during intermediate evaluation, and prior to surgery. In this study, we characterized the value of gene profile mutation and circulating tumor DNA (ctDNA) in combination with clinical characteristics in the prediction of pCR before surgery and investigated the prognostic prediction. The median follow-up time for survival analysis was 898 days. RESULTS: Firstly, we constructed a predictive NAC response model including five single nucleotide variant (SNV) mutations (TP53, SETBP1, PIK3CA, NOTCH4 and MSH2) and four copy number variation (CNV) mutations (FOXP1-gain, EGFR-gain, IL7R-gain, and NFKB1A-gain) in the breast tumor, combined with three clinical factors (luminal A, Her2 and Ki67 status). The tumor prediction model showed good discrimination of chemotherapy sensitivity for pCR and non-pCR with an AUC of 0.871 (95% CI, 0.797-0.927) in the training set, 0.771 (95% CI, 0.649-0.883) in the test set, and 0.726 (95% CI, 0.556-0.865) in an extra test set. This tumor prediction model can also effectively predict the prognosis of disease-free survival (DFS) with an AUC of 0.749 at 1 year and 0.830 at 3 years. We further screened the genes from the tumor prediction model to establish a unique personalized panel consisting of 9 individual somatic mutation genes to detect and analyze ctDNA. It was found that ctDNA positivity decreased with the passage of time during NAC, and ctDNA status can predict NAC response and metastasis recurrence. Finally, we constructed the chemotherapy prediction model combined with the tumor prediction model and pretreatment ctDNA levels, which has a better prediction effect of pCR with the AUC value of 0.961. CONCLUSIONS: In this study, we established a chemotherapy predictive model with a non-invasive tool that is built based on genomic features, ctDNA status, as well as clinical characteristics for predicting pCR to recognize the responders and non-responders to NAC, and also predicting prognosis for DFS in breast cancer. Adding pretreatment ctDNA levels to a model containing gene profile mutation and clinical characteristics significantly improves stratification over the clinical variables alone.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Terapia Neoadjuvante , Variações do Número de Cópias de DNA , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Medição de Risco , Proteínas Repressoras/genética , Proteínas Repressoras/uso terapêutico , Fatores de Transcrição Forkhead
11.
Toxicol Appl Pharmacol ; 478: 116698, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37742871

RESUMO

We managed to explore the function of HFY-4A, a novel histone deacetylases (HDACs) inhibitor, on breast cancer as well as its potential mechanisms. MCF7 and T47D cells were treated with 0.8, 1.6 or 3.2 µM HFY-4A for 0-72 h, following of which CCK-8, colony formation, EdU staining, flow cytometry, Transwell, and wound healing assays were carried out. Western blot, immunohistochemistry, and ELISA were conducted for assaying the expression of immunogenic cell death (ICD)-related proteins. The interaction between HFY-4A, HDAC1, and tumor suppressor candidate 2 (TUSC2) was evaluated by chromatin immunoprecipitation assay. Further, the function of HFY-4A in breast cancer progression in vivo was evaluated using xenograft mouse models. HFY-4A inhibited the proliferation, migration, and invasion, and induced apoptosis of breast cancer cells in a dose-dependent manner. HFY-4A dose-dependently caused the ICD of breast cancer cells, as evidenced by the significant high levels of high-mobility group box 1 (HMGB1), calreticulin (CRT), heat shock protein 70 (HSP70), and HSP90. Interestingly, HFY-4A could facilitate TUSC2 transcription by promoting acetylation of histones on the TUSC2 promoter. The results of rescue assays revealed that HFY-4A repressed proliferation and mobility, but enhanced apoptosis and ICD through facilitating TUSC2 transcription in breast cancer. In breast cancer xenograft mouse models, HFY-4A was verified to inhibit tumor growth via upregulating TUSC2. HFY-4A could inhibit breast cancer cell proliferation and mobility, and enhanced apoptosis and ICD through facilitating TUSC2 transcription.


Assuntos
Neoplasias da Mama , Humanos , Animais , Camundongos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Morte Celular Imunogênica , Linhagem Celular Tumoral , Apoptose , Modelos Animais de Doenças , Proliferação de Células , Proteínas Supressoras de Tumor/metabolismo
12.
Cancer Cell Int ; 23(1): 83, 2023 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-37120513

RESUMO

BACKGROUND: Reprogrammed metabolic network is a key hallmark of cancer. Profiling cancer metabolic alterations with spatial signatures not only provides clues for understanding cancer biochemical heterogeneity, but also helps to decipher the possible roles of metabolic reprogramming in cancer development. METHODS: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technique was used to characterize the expressions of fatty acids in breast cancer tissues. Specific immunofluorescence staining was further carried out to investigate the expressions of fatty acid synthesis-related enzymes. RESULTS: The distributions of 23 fatty acids in breast cancer tissues have been mapped, and the levels of most fatty acids in cancer tissues are significantly higher than those in adjacent normal tissues. Two metabolic enzymes, fatty acid synthase (FASN) and acetyl CoA carboxylase (ACC), which being involved in the de novo synthesis of fatty acid were found to be up-regulated in breast cancer. Targeting the up-regulation of FASN and ACC is an effective approach to limiting the growth, proliferation, and metastasis of breast cancer cells. CONCLUSIONS: These spatially resolved findings enhance our understanding of cancer metabolic reprogramming and give an insight into the exploration of metabolic vulnerabilities for better cancer treatment.

13.
J Chem Phys ; 158(18)2023 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-37154282

RESUMO

We demonstrate a methodology for computationally investigating the mechanical response of a pure molten lead surface system to the lateral mechanical cyclic loads and try to answer the following question: how does the dynamically driven liquid surface system follow the classical physics of the elastic-driven oscillation? The steady-state oscillation of the dynamic surface tension (or excess stress) under cyclic load, including the excitation of high-frequency vibration mode at different driving frequencies and amplitudes, was compared with the classical theory of a single-body driven damped oscillator. Under the highest studied frequency (50 GHz) and amplitude (5%) of the load, the increase of in (mean value) dynamic surface tension could reach ∼5%. The peak and trough values of the instantaneous dynamic surface tension could reach (up to) 40% increase and (up to) 20% decrease compared to the equilibrium surface tension, respectively. The extracted generalized natural frequencies seem to be intimately related to the intrinsic timescales of the atomic temporal-spatial correlation functions of the liquids both in the bulk region and in the outermost surface layers. These insights uncovered could be helpful for quantitative manipulation of the liquid surface using ultrafast shockwaves or laser pulses.

14.
World J Surg Oncol ; 21(1): 296, 2023 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-37723497

RESUMO

BACKGROUND: Although neoadjuvant trastuzumab and pertuzumab (HP)-based regimens are recommended for human epidermal receptor-positive (HER2 +)/lymph node-positive (N +) breast cancer (BC) patients according to NCCN guidelines, it is undeniable that many patients achieved pathological complete response (pCR) after trastuzumab (H)-based regimens without adding pertuzumab to treatment. Patients who specifically benefit from pertuzumab must be identified. The aim of this retrospective study was to evaluate progesterone receptor (PR) status as a predictor of response to the addition of pertuzumab in HER2 + /N + breast cancer. METHODS: One hundred forty-two patients who were diagnosed as HER2 + /N + BC without distant metastasis and followed by neoadjuvant HP-based or H-based therapy were retrospectively included. The endpoints were pCR and disease-free survival (DFS) times. RESULTS: In total, the pCR occurred in 25 of 87 patients (28.74%) in group H compared with 32 of 55 (58.18%) in group HP. The results revealed that hormone receptor (HR) status was significantly different on pCR in group HP. The odds of pCR for patients who have HR-positive tumors were 0.160 times (P = 0.011) that for patients with HR-negative tumors by multivariable analysis. Moreover, a similar probability of PR-positive (PR +) patients, whatever estrogen receptor (ER) status was, achieving pCR in group HP was observed. The ROC curves showed different anti-HER2 regimens provide worst predictive value in the PR + cohort (N = AUC = 0.521, 95% CI: 0.348-0.694, P = 0.813) compared with the overall cohort (AUC = 0.644, 95% CI: 0.550-0.738, P = 0.004) and ER + cohort (AUC: 0.559, 95% CI: 0.405-0.713, P = 0.451). And PR status (AUC = 0.760, 95% CI: 0.626-0.894, P = 0.001) had a greater predictive value than ER status (AUC = 0.658, 95% CI: 0.508-0.807, P = 0.048) in group HP. DFS analyses were done on 141 patients. Although ER and PR status did not show significant difference in group HP (P = 0.789 and 0.088, respectively), HP-based therapy contributed to better DFS in the ER - and PR - cohorts (P = 0.035 and 0.015, respectively). CONCLUSIONS: Compared with ER status, PR status might be a more valuable factor predicting the efficacy of adding pertuzumab into neoadjuvant therapy for HER2 + /N + BC. PR + patients benefit little from the addition of pertuzumab.


Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Metástase Linfática , Trastuzumab/uso terapêutico , China/epidemiologia , Linfonodos
15.
J Integr Neurosci ; 22(6): 138, 2023 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-38176925

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a common progressive neurodegenerative disease. The Ubiquitin-Protease system (UPS), which plays important roles in maintaining protein homeostasis in eukaryotic cells, is involved in the development of AD. This study sought to identify differential UPS-related genes (UPGs) in AD patients by using bioinformatic methods, reveal potential biomarkers for early detection of AD, and investigate the association between the identified biomarkers and immune cell infiltration in AD. METHODS: The differentially expressed UPGs were screened with bioinformatics analyses using the Gene Expression Omnibus (GEO) database. A weighted gene co-expression network analysis (WGCNA) analysis was performed to explore the key gene modules associated with AD. A Single-sample Gene Set Enrichment Analysis (ssGSEA) analysis was peformed to explore the patterns of immune cells in the brain tissue of AD patients. Real-time quantitative PCR (RT-qPCR) was performed to examine the expression of hub genes in blood samples from healthy controls and AD patients. RESULTS: In this study, we identified four UPGs (USP3, HECW2, PSMB7, and UBE2V1) using multiple bioinformatic analyses. Furthermore, three UPGs (USP3, HECW2, PSMB7) that are strongly correlated with the clinical features of AD were used to construct risk score prediction markers to diagnose and predict the severity of AD. Subsequently, we analyzed the patterns of immune cells in the brain tissue of AD patients and the associations between immune cells and the three key UPGs. Finally, the risk score model was verified in several datasets of AD and showed good accuracy. CONCLUSIONS: Three key UPGs are identified as potential biomarker for AD patients. These genes may provide new targets for the early identification of AD patients.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Biomarcadores , Biologia Computacional , Ubiquitinas , Ubiquitina-Proteína Ligases , Proteases Específicas de Ubiquitina
16.
FASEB J ; 35(4): e21531, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33769605

RESUMO

Lymphangiogenesis is thought to contribute to promote tumor cells to enter lymphatic vessels and plant at a secondary site. Endothelial cells are the cornerstone of the generation of new lymphatic vessels. NADPH oxidase 4 (Nox4) is the most abundant one of NADPH oxidases in endothelial cells and the most studied one in relevance with cancer. Our purpose is to analyze the relationship between Nox4 and lymphangiogenesis and find out whether the newborn lymphatic vessels lead to cancer metastasis. We first explored the expression of Nox4 in lymphatic endothelial cells of primary invasive breast tumors and human normal mammary glands using GEO databases and found that Nox4 was upregulated in primary invasive breast tumors samples. In addition, its high expression correlated with lymph node metastasis in breast cancer patients. Nox4 could increase the tube formation and lymphatic vessel sprouting in a three-dimensional setting. In vivo, inhibition of Nox4 in 4T1 tumor-bearing mice could significantly decrease the tumor lymphangiogenesis and metastasis. Nox4 may increase tumor lymphangiogenesis via ROS/ERK/CCL21 pathway and attract CCR7-positive breast cancer cells to entry lymphatic vessels and distant organs. In conclusion, our results show that Nox4 is a factor that promotes lymphangiogenesis and is a potential target of antitumor metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Células Endoteliais/metabolismo , Linfangiogênese/fisiologia , Metástase Linfática/patologia , NADPH Oxidase 4/antagonistas & inibidores , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Humanos , Linfangiogênese/efeitos dos fármacos , Vasos Linfáticos/metabolismo , NADPH Oxidase 4/metabolismo
17.
J Chem Phys ; 157(13): 134703, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36208999

RESUMO

The equilibrium silica liquid-liquid interface between the high-density liquid (HDL) phase and the low-density liquid (LDL) phase is examined using molecular-dynamics simulation. The structure, thermodynamics, and dynamics within the interfacial region are characterized in detail and compared with previous studies on the liquid-liquid phase transition (LLPT) in bulk silica, as well as traditional crystal-melt interfaces. We find that the silica HDL-LDL interface exhibits a spatial fragile-to-strong transition across the interface. Calculations of dynamics properties reveal three types of dynamical heterogeneity hybridizing within the silica HDL-LDL interface. We also observe that as the interface is traversed from HDL to LDL, the Si/O coordination number ratio jumps to an unexpectedly large value, defining a thin region of the interface where HDL and LDL exhibit significant mixing. In addition, the LLPT phase coexistence is interpreted in the framework of the traditional thermodynamics of alloys and phase equilibria.

18.
World J Surg Oncol ; 20(1): 145, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35524309

RESUMO

BACKGROUND: With the development of laparoscopic techniques and the broad clinical application of various anastomotic types, anal-preserving low anterior rectal resection and ultra-low anterior rectal resection have been popularized. Some patients with rectal cancer have retained their anus and improved their quality of life. Nevertheless, the incidence of postoperative anastomotic stenosis remains high, and anastomotic occlusion is even rarer. CASE PRESENTATION: We report a case of anastomotic occlusion in a patient with rectal cancer, which occurred after undergoing laparoscopic low anterior rectal resection + prophylactic terminal ileal fistulation at our department. Under endoscopy, we used a small guidewire to break through the occluded anastomosis, thereby finding the lacuna. After endoscopic balloon dilation, digital anal dilatation, and continuous dilator-assisted dilation, the desired efficacy was achieved, ultimately recovering ileal stoma. Postoperative follow-up condition was generally acceptable, without symptoms like abdominal pain, bloating, or difficulty in defecation. CONCLUSION: Numerous factors cause postoperative anastomotic stenosis in patients with rectal cancer. Complete occlusion of anastomosis occurs relatively rare in clinical practice, and is challenging to treat. This case was our first attempt to remove the anastomotic occlusion successfully, which avoided re-operation or pain from the permanent fistula.


Assuntos
Laparoscopia , Neoplasias Retais , Anastomose Cirúrgica/efeitos adversos , Fístula Anastomótica/cirurgia , Constrição Patológica/etiologia , Constrição Patológica/cirurgia , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Complicações Pós-Operatórias/epidemiologia , Qualidade de Vida , Neoplasias Retais/complicações , Neoplasias Retais/cirurgia , Estudos Retrospectivos
19.
Nano Lett ; 21(9): 3805-3812, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33878871

RESUMO

Searching for highly efficient oxygen reduction reaction (ORR) electrocatalysts for fuel cell technology, in which the crystal structure plays a powerful role in regulating the electrocatalysis, is urgent yet challenging. Herein, we have explored the active and stable Pd-Se alloy electrocatalysts with controlled phase toward alkaline ORR. The phase-controlled Pd-Se nanoparticles (NPs) show interesting phase-dependent electrocatalytic performance, in which the Pd17Se15 NPs/C exhibits much better ORR performance than its counterpart, Pd7Se4 NPs/C, and the commercial Pd/C and Pt/C. Based on the detailed analysis, Pd in Pd17Se15 possesses more Se atom coordination and a higher valence state, thus providing a stronger capacity for the absorption of oxygenated species. DFT further reveals more charge transfer from the Pd17Se15 surface to the *OOH intermediate, which is the reason for the activity enhancement.

20.
Entropy (Basel) ; 25(1)2022 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-36673181

RESUMO

This work studies the first-order coherence of noisy multi-agent networks with multi-layered structures. The coherence, which is a sort of performance index of networks, can be seen as a sort of measurement for a system's robustness. Graph operations are applied to design the novel multi-layered networks, and a graph spectrum approach, along with analysis methods, is applied to derive the mathematical expression of the coherence, and the corresponding asymptotic results on the performance index have been obtained. In addition, the coherence of these non-isomorphic multi-layered networks with three different graph parameters are compared and analyzed. We find that, when the cardinalities of the vertex sets of corresponding counterpart layers are the same, the multi-layered topology class with a balanced, complete, multi-partite structure has the best robustness of all the considered networks, if the sufficient conditions for the node-related parameters hold. Finally, simulations are given to verify the asymptotic results.

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