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As a global public health problem, sedentary behavior has attracted more and more attention. Although numerous studies have demonstrated many benefits of green spaces to health, causal evidence on how green spaces affect people's sedentary behavior is scarce. This study used a natural experiment to evaluate the impact of greenway intervention on sedentary behavior. Two waves of data were collected in 2016 and 2019 (before and after the intervention) at East Lake Greenway (102-km-long) in Wuhan, China, with 1020 participants in 52 neighborhoods. We adopted three major methods to evaluate the impact of greenway intervention on sedentary behavior, including Propensity Score Matching and difference-in-difference (PSM-DID) method (with both individual and neighborhood variables to match samples), continuous treatment DID method (with distance to the greenway as the continuous treatment), and mediation analysis (with moderate to vigorous physical activity or MVPA, and walking time as the mediator). The results revealed that the greenway intervention significantly reduced participants' sedentary time and the intervention has a distance decay effect. The closer to the greenway, the greater decrease in sedentary time after the greenway opening. Furthermore, we found that MVPA and walking time mediate the impact of the greenway intervention on the change in sedentary behavior. The effect of greenway intervention was more beneficial for those under the age of 60, those who were employed, or those who were married. Our findings provided robust evidence that exposure to urban greenways affects sedentary behavior and such green infrastructures help protect public health in high-density urban areas.
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Chinese herbs have been used to treat small-cell lung cancer (SCLC) due to their low toxicity and significant efficacy. This study focused on oridonin, a natural compound extracted from Rabdosia rubescens, and aimed to investigate its potential antitumor activity on SCLC and to evaluate the synergistic effect of combining oridonin with other small molecules. In this study, oridonin exhibited a dual effect. At lower concentrations, it suppressed the cell viability of SCLC cells (H1688 and H446). At high concentrations, oridonin induced SCLC cell apoptosis, damaged HBE cells in vitro and compromised the function of the liver and heart in vivo. The lower concentration of oridonin induced autophagy by enhancing the expression of p62 and the LC3B-II/LC3B-I ratio. This phenomenon might be associated with the activation of the protein kinase RNA-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α)/growth arrest and DNA damage-inducible gene 153 (CHOP/GAD153) pathway. Therefore, the combined effect of oridonin with GSK2606414 or 3- methyladenine increased apoptosis in SCLC cells and reduced tumor growth. A similar phenomenon was observed after oridonin was combined with p62 or CHOP RNA interference treatment. Simultaneously, the combination of oridonin and GSK2606414 exhibited therapeutic efficacy without manifesting adverse effects. Our findings suggest that oridonin at lower concentrations can induce autophagy by activating the PERK/eIF2α/CHOP signaling pathway. The inhibition of the PERK/eIF2α/CHOP pathway could enhance oridonin therapeutic responses by triggering apoptosis. The novel therapeutic approach of combining oridonin with a PERK inhibitor is promising as a strategy for the treatment of SCLC.
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Apoptose , Autofagia , Diterpenos do Tipo Caurano , Fator de Iniciação 2 em Eucariotos , Neoplasias Pulmonares , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão , Fator de Transcrição CHOP , eIF-2 Quinase , Diterpenos do Tipo Caurano/farmacologia , Autofagia/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , eIF-2 Quinase/metabolismo , Apoptose/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Linhagem Celular Tumoral , Fator de Iniciação 2 em Eucariotos/metabolismo , Animais , Transdução de Sinais/efeitos dos fármacos , Camundongos Nus , Camundongos Endogâmicos BALB C , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , MasculinoRESUMO
Background and aim: Rivaroxaban is an emerging oral anticoagulant for postoperative anticoagulation after percutaneous left atrial appendage closure (LAAC). Because a once-daily dosing regimen of rivaroxaban causes fluctuations in the drug plasma concentration, we studied the feasibility and safety of twice-daily rivaroxaban as a postoperative anticoagulation regimen for patients with atrial fibrillation (AF) undergoing LAAC. Methods: This study involved patients with AF who underwent LAAC and took rivaroxaban postoperatively. A total of 326 patients who received a standard total dose (15 or 20 mg) of rivaroxaban based on their creatinine clearance rate were divided into the twice-daily (BID) rivaroxaban group (n = 208) and once-daily (QD) rivaroxaban group (n = 118) according to their anticoagulation strategy. Transesophageal echocardiography was recommended at 3-6 months postoperatively to check for device-related thrombosis (DRT). Clinical outcomes were evaluated during postoperative anticoagulation. Results: The median CHA2DS2-VASc score (4 [3, 5] vs. 4 [3, 5], p = 0.28) and HAS-BLED score (2 [2, 3] vs. 2 [2, 3], p = 0.48) were not significantly different between the groups. During the anticoagulation period (4.1 ± 0.7 vs. 4.1 ± 0.9 months, p = 0.58), 148 (71.2%) patients in the BID group and 75 (63.6%) in the QD group underwent follow-up transesophageal echocardiography. There were no statistically significant differences between the two groups in terms of DRT (1.4% vs. 2.7%, p = 0.60), minor bleeding (8.2% vs. 11.0%, p = 0.39), thromboembolic events (1.0% vs. 0.8%, p = 1.00), major bleeding (0.5% vs. 0.8%, p = 1.00), or death. Conclusion: A short course of twice-daily rivaroxaban following LAAC is a feasible alternative regimen with a low rate of major bleeding events, DRT, and thromboembolic events for patients with AF.
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BACKGROUND: The clinical data regarding the relationships between BMI and abdominal aortic aneurysm (AAA) are inconsistent, especially for the obese and overweight patients. The aims of this study were to determine whether obesity is associated with the presence of AAA and to investigate the quantitative relationship between BMI and the risk of AAA presence and postoperative mortality. MATERIALS AND METHODS: PubMed, Web of Science, and Embase databases were used to search for pertinent studies updated to December 2023. The pooled relative risk (RR) with 95% CI was estimated by conventional meta-analysis based on random effects model. Dose-response meta-analyses using robust-error meta-regression (REMR) model were conducted to quantify the associations between BMI and AAA outcome variables. Subgroup analysis, sensitivity analysis, and publication bias analysis were performed according to the characteristics of participants. RESULTS: Eighteen studies were included in our study. The meta-analysis showed a higher prevalence of AAA with a RR of 1.07 in patients with obesity. The dose-response meta-analysis revealed a nonlinear relationship between BMI and the risk of AAA presence. A 'U' shape curve reflecting the correlation between BMI and the risk of postoperative mortality in AAA patients was also uncovered, suggesting the 'safest' BMI interval (28.55, 31.05) with the minimal RR. CONCLUSIONS: Obesity is positively but nonlinearly correlated with the increased risk of AAA presence. BMI is related to AAA postoperative mortality in a 'U' shaped curve, with the lowest RR observed among patients suffering from overweight and obesity. These findings offer a preventive strategy for AAA morbidity and provide guidance for improving the prognosis in patients undergone AAA surgical repair.
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Aneurisma da Aorta Abdominal , Índice de Massa Corporal , Obesidade , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/mortalidade , Humanos , Obesidade/complicações , Fatores de Risco , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/etiologiaRESUMO
Mutations in the genes of tumor cells and the disorder of immune microenvironment are the main factors of tumor development. The sensitivity of tumor cells to chemotherapy drugs affect the treatment of tumor. Nuclear transcription factor E4BP4 is dysregulated in a variety of malignant tumors. It can suppress the transcription of NFKBIA, RASSF8, SOSTDC1, FOXO-induced genes (TRAIL, FAS, GADD45a and GADD45b) and Hepcidin, up-regulate RCAN1-1 and PRNP, activate mTOR and p38 in cancer cells. Also, E4BP4 can regulate tumor immune microenvironment. TGFb1/Smad3/E4BP4/ IFNγ axis in NK cells plays an important role in antitumor immunotherapy. Over expression of E4BP4 inhibited the development of Th17 cells by directly binding to the RORγt promoter. Moreover, recent studies have shown that E4BP4 inhibited the expression of multidrug resistance genes. In this review, we summarize the molecular mechanism of E4BP4 in cancer cellular process, the effects of E4BP4 in cancer immunotherapy and antitumor drug resistance, to provide theoretical basis for tumor treatment strategies targeting E4BP4.
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Fatores de Transcrição de Zíper de Leucina Básica , Neoplasias , Humanos , Fatores de Transcrição de Zíper de Leucina Básica/genética , Imunoterapia , Células Matadoras Naturais , Neoplasias/genética , Fatores de Transcrição/genética , Microambiente TumoralRESUMO
An embedded obstacle-type micromixer-concentration gradient generator based on capillary self-driven is proposed and studied. Herringbone structure (HS) for mixing and palisade-shape small channels at the outlet are designed in the device (named HS). Simulation and experimentation are done to study the liquid mixing efficiency in the small channels and concentration gradient at the outlet, and the experimental results agree with the simulation results. For three cases of liquid dripping (sequential, reverse, and delayed drippings), mixing analysis shows that the mixing efficiency increases along both mixing channel and palisade length, and is high in the middle small channel of the palisade-shape area and low on both sides. An obvious concentration gradient at the outlet can form compared with the device without the palisade-shape area. Finally, water pH value detection is done as one of the applications of HS. This study can provide guidance for the application of HS in biochemical detection, cell research, drug screening, etc. based on the capillary-driven effect.
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Simulação por ComputadorRESUMO
BACKGROUND: Advances in microscopic and endoscopic surgical techniques have outpaced traditional classification and transcranial surgical strategies, especially with reference to the treatment of trigeminal schwannomas (TSs). A modified TS classification is proposed and appropriate surgical strategies are discussed. METHODS: The cases of 93 patients who underwent surgical treatment in Beijing Tiantan Hospital in the previous 6 years were analyzed retrospectively, and a literature review was conducted. RESULTS: Classification is based on surgical direction. Tumors were classified as follows: type A, backward orientation, located in the orbit or orbit and middle cranial fossa (8 cases, 8.6%); type B, upward orientation, located in the pterygopalatine fossa, infratemporal fossa or pterygopalatine fossa, infratemporal fossa, and middle cranial fossa (23 cases, 24.7%); type C, forward and backward orientations, located in the middle cranial fossa, posterior cranial fossa or both (58 cases, 62.4%); and type D, located in multiple regions (4 cases, 4.3%). 91.40% of patients underwent gross total resection (GTR) with 29 cases receiving endoscopic resection of whom 93.10% (27/29) experienced GTR. CONCLUSION: The 93 cases were satisfactorily divided into four types, according to tumor location and surgical orientation, enabling safe and effective removal by appropriate surgery.
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Neoplasias dos Nervos Cranianos , Neurilemoma , Humanos , Estudos Retrospectivos , Neoplasias dos Nervos Cranianos/cirurgia , Neoplasias dos Nervos Cranianos/patologia , Endoscopia , Órbita/patologia , Neurilemoma/cirurgiaRESUMO
Cholesterol is a critical molecule whose dysregulation in certain brain regions is related to multiple neurological disorders. It is of pathological importance to map the distribution of cholesterol in brain. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been widely used in the molecular imaging of metabolites at a high spatial resolution. However, it is challenging to analyze cholesterol by MALDI-MS due to its difficulty in ionization. Herein, we present for the first time a type of reactive matrix for MALDI-MS of cholesterol. Methylpyridinium carboxaldehydes react with cholesterol and other hydroxyl-containing sterols, which greatly enhanced both desorption and ionization and improved the limits of detection to the low µg/mL range. Compared with previous methods, our reactive matrix requires only one step of chemical derivatization and avoids time-consuming enzymatic reaction, which simplified the sample pretreatment. The reactive matrix was successfully used in mapping the distribution of cholesterol in brain tissue sections using MALDI-MS imaging. In summary, this work has provided a sensitive and simple method for the MALDI-MS analysis of cholesterol, has proposed a novel solution to visualize the distribution of sterol metabolites, and has great potential for applications in neurological and pathological studies.
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Fitosteróis , Esteróis , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Colesterol , EncéfaloRESUMO
Background and Objectives: With the growing incidence and disability associated with myocardial infarction (MI), there is an increasing focus on cardiac rehabilitation post-MI. Kuanxiongzhuyu decoction (KXZY), a traditional Chinese herbal formula, has been used in the rehabilitation of patients after MI. However, the chemical composition, protective effects, and underlying mechanism of KXZY remain unclear. Materials and Methods: In this study, the compounds in KXZY were identified using a high-performance liquid chromatography-mass spectrometry (HPLC-MS) analytical method. Based on the compounds identified in the KXZY, we predictively selected the potential targets of MI and then constructed a protein-protein interaction (PPI) network to identify the key targets. Furthermore, the DAVID database was used for the GO and KEGG analyses, and molecular docking was used to verify the key targets. Finally, the cardioprotective effects and mechanism of KXZY were investigated in post-MI mice. Results: A total of 193 chemical compounds of KXZY were identified by HPLC-MS. In total, 228 potential targets were obtained by the prediction analysis. The functional enrichment studies and PPI network showed that the targets were largely associated with AKT-pathway-related apoptosis. The molecular docking verified that isoguanosine and adenosine exhibited excellent binding to the AKT. In vivo, KXZY significantly alleviated cardiac dysfunction and suppressed AKT phosphorylation. Furthermore, KXZY significantly increased the expression of the antiapoptotic proteins Bcl-2 and Bcl-xl and decreased the expression of the proapoptotic protein BAD. Conclusions: In conclusion, the network pharmacological and experimental evidence suggests that KXZY manifests anti-cardiac dysfunction behavior by alleviating cardiomyocyte apoptosis via the AKT pathway in MI and, thus, holds promising therapeutic potential.
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Reabilitação Cardíaca , Infarto do Miocárdio , Humanos , Animais , Camundongos , Farmacologia em Rede , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-akt , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológicoRESUMO
Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and its ligand 1 (PD-L1), have improved the survival in multiple types of cancers; however, ICIs may cause cardiovascular toxicity. Although rare, ICI-mediated cardiotoxicity is an extremely serious complication with a relatively high mortality. In this review, we discuss the underlying mechanism and clinical manifestations of cardiovascular toxicity induced by ICIs. According to previous studies, multiple signaling pathways are involved in myocarditis induced by ICIs. Further, we summarize the clinical trials of drugs for the treatment of ICI-associated myocarditis. Although these drugs have shown the beneficial effects of alleviating cardiac function and reducing mortality rates, their efficacy is not optimal. Finally, we discuss the therapeutic potential of some novel compounds as well as the underlying mechanisms of their action.
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BACKGROUND: As the efficacy of programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors combined with chemotherapy in curing breast cancer is still controversial, this meta-analysis compares the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy and chemotherapy alone in the treatment of breast cancer, which provides guidance for the clinical treatment. METHODS: Relevant studies published as of April 2022 in the various databases including EMBASE, PubMed, and Cochrane Library were selected. Randomized controlled trials (RCTs) in which control patients underwent chemotherapy alone and experimental group patients underwent combination chemotherapy and PD-1/PD-L1 inhibitor treatment were included in this investigation. Investigations without complete information, researches from which information could not be extracted, duplicate articles, animal studies, review articles, and systematic reviews were excluded. STATA 15.1 was employed for all statistical analyses. RESULTS: In total, eight eligible studies were identified, revealing that combination chemotherapy and PD-1/PD-L1 inhibitor treatment was linked to significant increases in progression-free survival (PFS) relative to chemotherapy alone (hazard ratio [HR] = 0.83, 95% confidence interval [CI]: 0.70-0.99, P = 0.032) but not overall survival (HR = 0.92, 95% CI: 0.80-1.06, P = 0.273). Pooled adverse event rates were also increased within the group of combination treatment relative to the chemotherapy group (risk ratio [RR] = 1.08, 95% CI: 1.03-1.14, P = 0.002). Specifically, nausea rates were lesser within the group of combination treatment relative to the group of chemotherapy (RR = 0.48, 95% CI: 0.25-0.92, P = 0.026). Subgroup analyses indicated that the PFS of patients who underwent combination atezolizumab or pembrolizumab and chemotherapy treatment were substantially longer than those of patients who underwent chemotherapy alone (HR = 0.79, 95% CI: 0.69-0.89, P ≤0.001; HR = 0.79, 95% CI: 0.67-0.92, P = 0.002). CONCLUSIONS: The pooled results suggest that combination chemotherapy and PD-1/PD-L1 inhibitor treatment approaches help prolong PFS in breast cancer patients, but have no statistically significant effect on overall survival (OS). Additionally, combination therapy can significantly improve complete response rate (CRR) compared with chemotherapy alone. However, combination therapy was associated with greater rates of adverse events.
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Neoplasias da Mama , Inibidores de Checkpoint Imunológico , Humanos , Antígeno B7-H1/antagonistas & inibidores , Quimioterapia Combinada , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológicoRESUMO
Chemotherapy remains a critical component of triple-negative breast cancer (TNBC) treatment; however, patients often develop resistance to chemotherapeutic agents. Accumulating evidence indicates that deubiquitylases (DUBs) play pivotal roles in regulating cell proliferation, differentiation, apoptosis, and tumorigenesis. Deubiquitylase OTUD1 is considered a tumor suppressor in various cancers, yet its role in doxorubicin sensitivity in breast cancer patients remains inadequately understood. In this study, we investigated the expression levels and prognostic role of OTUD1 in breast cancer. Our findings demonstrated that OTUD1 was downregulated in TNBC, and lower OTUD1 expression levels were correlated with poor prognosis. We utilized the CCK-8 cell viability assay, flow cytometric analysis, and a TNBC mouse xenograft model to examine the influence of OTUD1 on doxorubicin (DOX) chemotherapy sensitivity in vitro and in vivo. Western blot and immunohistochemistry were employed to explore the correlation between OTUD1 and P16. Our results indicated that upregulation of OTUD1 expression inhibits TNBC cell proliferation and enhances its sensitivity to doxorubicin. Additionally, rescue experiments confirmed that the chemosensitizing effect of OTUD1 overexpression could be reversed by the inhibition of P16. Therefore, our findings reveal that OTUD1 sensitizes TNBC cells to DOX by upregulating P16 expression, suggesting a potential new diagnostic biomarker and therapeutic target for the future treatment of TNBC.
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Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Apoptose , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteases Específicas de UbiquitinaRESUMO
Medulloblastoma (MB) is the commonest primary malignant brain cancer. The current treatment of MB is usually surgical resection combined with radiotherapy or chemotherapy. Although great progress has been made in the clinical management of MB, tumor metastasis and recurrence are still the main cause of death. Therefore, definitive and timely diagnosis is of great importance for improving therapeutic effects on MB. In 2016, the World Health Organization (WHO) divided MB into four subtypes: wingless-type mouse mammary tumor virus integration site (WNT), sonic hedgehog (SHH), non-WNT/non-SHH group 3, and group 4. Each subtype of MB has a unique profile in copy number variation, DNA alteration, gene transcription, or post-transcriptional/translational modification, all of which are associated with different biological manifestations, clinical features, and prognosis. This article reviewed the research progress of different molecular pathology markers in MB and summarized some targeted drugs against these molecular markers, hoping to stimulate the clinical application of these molecular markers in the classification, diagnosis, and treatment of MB.
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Dextran (Dex) and poly(ethylene glycol) (PEG)-based aqueous emulsions were stabilized using the self-assembled chitosan colloidal particles (CS CPs). Besides, the effects of pH, CS CPs concentration, polymer concentration, volume ratio of PEG solution to Dex solution, temperature, homogenizing speed and homogenizing time on the property of the W/W emulsions were investigated, respectively. In order to enhance the stability of the PEG-Dex emulsion, sodium tripolyphosphate was used to cross-link the CS CPs at the interface of emulsion droplets, which resulted in the stability duration for >1 year. Finally, the CS CPs were used as a support to immobilize urease and bovine serum albumin and a stabilizer to prepare W/W emulsion, which were then adopted as a catalysis system and as a spinning solution to fabricate drug-loaded nanofiber. This strategy potentially provides a new opportunity to encapsulate the active molecules at the water-water interface, and enrich the types of usable active molecules in the encapsulation in the W/W emulsions.
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Myrrh is the dried resin of Commiphora Myrrh Engl., which exerts anticancer properties. However, its effects and molecular mechanisms in triple-negative breast cancer (TNBC) remain unclear. In this study, we used network pharmacology to screen Z-Guggulsterone (Z-GS) as a characteristic active component of myrrh. Cell Counting Kit-8 proliferation assays showed that Z-GS inhibited proliferation of the TNBC cell lines MDA-MB-468 and BT-549. Transwell assays also showed that Z-GS inhibited TNBC migration and invasion phenotypes. Our network pharmacology combined with RNA-sequencing analyses showed that Z-GS affected cell cycle and apoptosis processes in TNBC cells, mainly via p53 signaling, to regulate key CCNB1 (cyclin B1), PLK1 (polo-like kinase 1), and p53 targets. Flow cytometry revealed that Z-GS arrested the cell cycle at the G2/M phase and increased apoptosis in TNBC cells. Western blotting and quantitative real-time polymerase chain reaction studies confirmed that Z-GS functioned via the p53-mediated downregulation of CCNB1 and PLK1 expression. In vivo studies showed that Z-GS effectively inhibited TNBC progression. Collectively, Z-GS exhibited potential anti-TNBC activity and may functions via the p53/CCNB1/PLK1 pathway.
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OBJECTIVE: To evaluate the value of texture analysis of routine MRI image in peritumoral edema of differentiating diagnosis between glioblastoma (GBM) and primary brain lymphoma (PBL). METHODS: The MRI imaging data of 22 patients with glioblastoma and 21 patients with PBL who were hospitalized in our hospital from January 2010 to October 2018 were selected. All the patients were pathologically diagnosed as glioblastoma or PBL, and MRI plain scan and enhanced examination were performed before operation. FireVoxel software was used to delineate the region of interest (ROI) on the most obvious level of peritumoral edema based on T1WI enhancement. Texture parameters were extracted and compared between glioblastoma and PBL. RESULTS: In the glioblastoma group, the inhomogeneity, kurtosis and entropy texture parameters were statistically different from those in the PBL group. The entropy parameter area under the curve (AUC) (0.903) was significantly better than the kurtosis parameter AUC (0.859) and the inhomogeneity parameter AUC (0.729). When the entropy parameter Cut-off point = 3.883, the sensitivity, specificity and accuracy of glioblastoma and PBL were 85.7, 86.4 and 86.0%, respectively, by differential diagnosis. CONCLUSION: Texture analysis of tumor peritumoral edema provided quantifiable information, which might be a new method for differentiating glioblastoma from PBL.
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Neoplasias Encefálicas , Glioblastoma , Linfoma , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Linfoma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Diagnóstico Diferencial , Edema/diagnóstico , Encéfalo/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: The data in the real-world setting on breast pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for hormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+, HER2-) breast cancer (BC) is limited. The present study aims to screen for some predictors and investigate the prognostic significance of breast pCR after NAC in HR+, HER2- BC in China. METHODS: This was a multicenter, retrospective study. In this study, three hundred eighty-four HR+, HER2- BC patients who received NAC were enrolled between 2010 and 2016 from Shanghai Jiaotong University Breast Cancer Database (SJTU-BCDB). These patients were dichotomized according to the presence of breast pCR after NAC. Logistic analysis was used to screen for predictors associated with breast pCR. Kaplan-Meier (K-M) curve and a propensity score matching (PSM) analysis were performed to compare the disease-free survival (DFS) between the two groups. Cox regression was used to analyze the prognostic significance of breast pCR on DFS in HR+, HER2- BC. A nomogram model was established to predict the probability of DFS at 1, 3, and 5 years after NAC. RESULTS: Fifty-seven patients (14.8%) achieved breast pCR. Univariate analysis showed that tumor size, estrogen receptor (ER), progesterone receptor (PR), and Ki67 were associated with breast pCR. Further, multivariate analysis showed that tumor size, PR, and Ki67 remained statistically significant. K-M curves showed a statistical difference between the breast pCR and non-pCR groups before PSM (p = 0.047), and a more significant difference was shown after PSM (p = 0.033). Cox regression after PSM suggested that breast pCR, adjuvant ET, clinical T stage, and Ki67 status were the significant predictive factors for DFS in HR+, HER2- BC patients. The adjusted hazards ratio (aHR) for breast pCR was 0.228 (95% CI, 0.070~0.739; p = 0.014), for adjuvant endocrine therapy was 0.217 (95% CI, 0.059~0.801; p = 0.022), for Ki67 was 1.027 (95% CI, 1.003~1.052; p = 0.027), for cT stages 2 and 3 compared with 1, the values were 1.331 (95% CI, 0.170~10.389), and 4.699 (95% CI, 0.537~41.142), respectively (p = 0.043). A nomogram was built based on these significant predictors, providing an integrated probability of DFS at 1, 3, and 5 years. The values of area under the receiver operating characteristic (ROC) curve (AUC) were 0.967, 0.991, and 0.787, at 1 year, 3 years, and 5 years, respectively, demonstrating the ability of the nomogram to predict the DFS. CONCLUSIONS: This real-world study demonstrates that tumor size, PR, and Ki67 were independent predictive factors for breast pCR in HR+, HER2- BC. Breast pCR after NAC was an independent predictor for DFS in HR+, HER2- patients, regardless of a change in nodes. Furthermore, the nomogram built in our study could predict the probability of individualized DFS in HR+, HER2- BC patients.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , China/epidemiologia , Intervalo Livre de Doença , Receptores ErbB , Feminino , Humanos , Antígeno Ki-67 , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio , Receptores de Progesterona , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Model-based reinforcement learning enables an agent to learn in variable environments and tasks by optimizing its actions based on the predicted states and outcomes. This mechanism has also been considered in the brain. However, exactly how the brain selects an appropriate model for confronting environments has remained unclear. Here, we investigated the model selection algorithm in the human brain during a reinforcement learning task. One primary theory of model selection in the brain is based on sensory prediction errors. Here, we compared this theory with an alternative possibility of internal model selection with reward prediction errors. To compare these two theories, we devised a switching experiment from a first-order Markov decision process to a second-order Markov decision process that provides either reward- or sensory prediction error regarding environmental change. We tested two representative computational models driven by different prediction errors. One is the sensory prediction-error-driven Bayesian algorithm, which has been discussed as a representative internal model selection algorithm in the animal reinforcement learning task. The other is the reward-prediction-error-driven policy gradient algorithm. We compared the simulation results of these two computational models with human reinforcement learning behaviors. The model fitting result supports that the policy gradient algorithm is preferable to the Bayesian algorithm. This suggests that the human brain employs the reward prediction error to select an appropriate internal model in the reinforcement learning task.