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1.
Cancer Med ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643330

RESUMO

BACKGROUND: With life span extending, breast cancer (BC) survivors may face the possibility of developing second primary cancer (SPC) and considerably shorten survivorship. However, little is known about multiple primary cancer (MPC) patients with nonmetastatic breast cancer as a first primary malignancy (BCFPM). METHODS: Here, we retrospectively analyzed data on cancer survivors with BCFPM diagnosed between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. The prognostic factors for breast cancer-specific survival (BCSS) were ascertained by the stepwise regression analysis and a competing risk model, and were integrated to the establishment of prognostic nomogram, of which the accuracy was measured by the calibration curve and the concordance index (C-index). RESULTS: In total, 8616 patients were identified with 4.6% of 3-year breast cancer- specific death (BCSD) and 8.6% of 5-year BCSD. The most common SPC among BCFPM patients were female BC and lung cancer. Besides, the median latency time between BC and SPC was 22 months. At a ratio of 7:3, all patients were randomly categorized into a training cohort (n = 6032) and a validation cohort (n = 2584). By a proportional subdistribution hazards regression analysis, the following factors were considered to own independent prognostic abilities of BCSS: subtypes, grade, T classification, N classification, radiation, and sites of SPC. The nomogram could accurately predict 3-year and 5-year breast cancer-associated survival of BCFPM patients with high internal and external validated C-index, 0.715 (95% CI, 0.691-0.739), and 0.683 (95% CI, 0.642-0.724), respectively. CONCLUSIONS: BC survivors remained a high risk of developing SPC and considerably shortened survival time. In this study, a favorable nomogram was constructed to as a prediction model for 3-year and 5-year BCSS of BCFPM patients, largely intending to prolong the life of these patients by assisting clinicians to make individualized follow-up plans.

2.
Talanta ; 235: 122810, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517667

RESUMO

MicroRNAs (miRNAs) are currently recognized as novel biomarkers for cancer early diagnosis, therapy selection, and progression monitoring. Herein, we developed an ultrasensitive and label-free homogeneous colorimetric strategy for miRNA detection based on engineering entropy-driven amplification (EDA) coupled with nicking enzyme-assisted AuNP aggregation. In our design, the target miRNA could specifically trigger the EDA recycling process. One of the EDA products could open the hairpin probe and form a dual strand containing a nicking endonuclease (Nb.BbvCl) cleavage region. After adding nicking endonuclease in the sensing solution, the product DNA fragments could act as two linkers, inducing the aggregation of ssDNA-modified AuNPs. Simultaneously, the liberating complementary strands continued to cyclic hybridization with the hairpin probe. This multiple signal amplification colorimetric strategy showed a wide linear range from 10 fM to 100 pM with a much lower detection limit of 3.13 fM for miRNA let-7a, which also performed well in a complex sample matrix. Most importantly, the naked eye could clearly distinguish the 10 fM color change caused by let-7a to be measured. Moreover, this approach could easily extend to multiple miRNAs with target-specific sequence substitutions. Therefore, this ultrasensitive visual strategy for miRNA demonstrated attractive potentials for promising applications in clinical diagnosis.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , MicroRNAs , Entropia , Ouro , Limite de Detecção , MicroRNAs/genética , Técnicas de Amplificação de Ácido Nucleico
3.
Cancer Med ; 10(19): 6744-6761, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34472719

RESUMO

BACKGROUND: Anthracycline-based chemotherapy (ABC) is one of the standard therapies against breast cancer. However, few guidelines are currently available to optimize the use of ABC. Therefore, the present analysis aimed at determining the profile and treatment patterns of ABC and the association of clinicopathological characteristics with ABC selection. METHODS: We retrospectively analyzed the data of a nation-wide multicenter epidemiological study, which collected the medical records of breast cancer patients receiving chemotherapy in different settings from seven geographic regions in China (NCT03047889). RESULTS: In total, 3393 patients were included, with 2917 treated with ABC. Among them, 553 (89.8%), 2165 (81.7%), and 814 (25.7%) were subjected to ABC as neoadjuvant, adjuvant, and advanced chemotherapy, respectively. The most frequently used regimens were anthracycline-taxane-based combinations for neo- and adjuvant chemotherapy, along with taxanes and oral fluorouracils for the palliative stages. In the overall cohort, patients aged < 40 or 40-65 (p < 0.001), in premenopause (p < 0.001), without comorbidities (p = 0.016), with invasive ductal carcinoma (p= 0.001), high lymph node involvement (p < 0.001), in the pTNM stage II, III, or IV versus stage I (p < 0.001), subjected to mastectomy (p < 0.001) or subjected to sentinel lymph node biopsy combined with axillary lymph node dissection (p = 0.044), or with a decreased disease-free survival (p < 0.001) were more likely to be recommended to ABC. CONCLUSION: Taken together, ABC remained the mainstay of breast cancer treatment, especially in neo and adjuvant therapy. ABC was mainly used as a combination therapy, and the correlation between influencing factors and ABC choice varied during different settings, indicating the preference and different perspectives of medication considered by medical oncologists regarding the use ABC in China.

4.
Anal Chem ; 93(32): 11159-11166, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34347435

RESUMO

Phenotypic plasticity is an emerging paradigm for providing biological and clinical insights into cancer initiation, progression, and resistance to therapy. However, it is a great challenge to track phenotypic information on live cells with high levels of sensitivity, specificity, and simplicity, when a specific cancer-cell subset is being targeted. In this work, we have successfully achieved cascade assembly of nanoparticles on the surface of specific cancer cells by designing a dual-aptamer-weaved molecular AND logic system. Taking advantage of spatial addressability, precise controllability, and targeting recognition of the nanostructure assemblies, we can precisely label the target-cell subset in a large population of similar cells and rapidly obtain phenotypic information in response to the surface changes of captured cancer cells. Without sophisticated instruments, we can know the phenotypic information on HepG2 cells in whole blood with a high level of sensitivity and rapid naked-eye tracking of on-cell phenotype changes of HepG2 cells undergoing epithelial-mesenchymal transition.


Assuntos
Aptâmeros de Nucleotídeos , Nanoestruturas , Tecnologia de Rastreamento Ocular , Células Hep G2 , Humanos , Fenótipo
5.
ACS Appl Mater Interfaces ; 13(31): 36919-36925, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34328724

RESUMO

The structures assembled by peptides have attracted great attention due to their unique physicochemical properties. Moreover, the co-assembly of peptides with additional components can endow the structures with extended functions. In this work, we have explored the co-assembly of peptides and carbon nanodots (CNDs) by taking advantage of their non-covalent binding; thus, the obtained structure may show both the recognition capability of peptides and the catalytic activity of CNDs. Therefore, we have further used the assembled structure for the sensitive analysis of transglutaminase 2 with a low detection limit of 0.25 pg/mL. By simply replacing the peptide sequences or the nanomaterials, the strategy proposed in this work can be developed as a universal model to build the co-assemblies of peptides and nanomaterials, thus leading to their broader applications in biological and biomedical research.

6.
Chem Commun (Camb) ; 57(53): 6522-6525, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34105555

RESUMO

We have proposed a simple electrochemical method in this work for the assay of tumor cells through their own steric hindrance effect. Specifically, tumor cells can block the catalysis of terminal deoxynucleotidyl transferase to the aptamer previously immobilized on the electrode surface. By making use of the hindrance effect, cancer cells can be quantitatively analyzed in the range from 1.6 × 102 to 1.6 × 106 cells per mL without complicated design or cumbersome operation, while the detection limit can be about 53 cells per mL. This method can also show satisfactory performance in complex environments, indicating its potential in clinical application.


Assuntos
Separação Celular/métodos , Eletroquímica/métodos , Linhagem Celular Tumoral , Eletrodos , Humanos , Limite de Detecção
7.
Talanta ; 232: 122451, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074435

RESUMO

The superior supramolecular recognition ability of macrocyclic compounds will enhance the sensitivity and selectivity of electrochemical detection, which has a great application potential in electrochemical sensing. Herein, we developed a novel electrochemical aptasensor based on the specific host-guest interactions between cucurbit [7]uril and ferrocene (Fc) for capture, determination and release of exosomes. Macrocyclic compounds, cucurbit [7]uril is modified on the surface of the gold nanoparticles composed electrode by self-assembling. CD63 aptamer linked ferrocene is introduced into this platform to capture exosomes specifically by CD63 protein on the exosomes. The dual specificity of macrocyclic compounds and aptamers enables highly selective and sensitive electrochemical detection of exosomes. The limit of detection (LOD) was 482 particles µL-1. In addition, the captured exosomes could be released on demand in a very mild manner through aminoferrocene (NH2-Fc) because of its higher affinity to cucurbit [7]uril. The proposed electrochemical aptasensor showed good performance in detecting exosomes even in plasma samples, thus demonstrating its great potential in early clinical diagnosis. Simultaneously, exosomes could be released undamaged by this protocol, exhibiting good applicability in comprehensive studies of exosomes. Moreover, this strategy can be applied to other target biomolecules by changing the recognition pairs.

8.
Anal Chem ; 93(19): 7250-7257, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33944568

RESUMO

Extensive attention has been recently focused on designing signal adjustable biosensors. However, there are limited approaches available in this field. In this work, to visually track lysosomes with high contrast, we used the i-motif structure as a pH-responsive unit and proposed a novel strategy to regulate the fluorescence resonance energy transfer (FRET) response of the pH sensor. By simply splitting the i-motif into two parts and modulating the split parameters, we can tune the pH transition midpoint (pHt) from 5.71 to 6.81 and the signal-to-noise ratio (S/N) from 1.94 to 18.11. To facilitate the lysosome tracking, we combined the i-motif split design with tetrahedral DNA (Td). The obtained pH nanosensor (pH-Td) displays appropriate pHt (6.12) to trace lysosomes with high S/N (10.3). Benefited from the improved stability, the superior cell uptake and lysosomal location of pH-Td, the visualization of the distribution of lysosomes, the lysosome-mitochondria interaction, and the pH changes of lysosomes in response to different stimuli were successfully achieved in NIH 3T3 cells. We believe that the design concept of controlling the split sequence distance will provide a novel insight into the design of i-motif-based nanosensors and even inspire the construction of smart DNA nanodevices for sensing, disease diagnosis, and controllable drug delivery.


Assuntos
Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes , Animais , DNA , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Lisossomos , Camundongos
9.
J Exp Clin Cancer Res ; 40(1): 142, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906694

RESUMO

Breast cancer is a heterogeneous disease with a complex microenvironment consisting of tumor cells, immune cells, fibroblasts and vascular cells. These cancer-associated cells shape the tumor microenvironment (TME) and influence the progression of breast cancer and the therapeutic responses in patients. The exact composition of the intra-tumoral cells is mixed as the highly heterogeneous and dynamic nature of the TME. Recent advances in single-cell technologies such as single-cell DNA sequencing (scDNA-seq), single-cell RNA sequencing (scRNA-seq) and mass cytometry have provided new insights into the phenotypic and functional diversity of tumor-infiltrating cells in breast cancer. In this review, we have outlined the recent progress in single-cell characterization of breast tumor ecosystems, and summarized the phenotypic diversity of intra-tumoral cells and their potential prognostic relevance.

10.
ACS Sens ; 6(4): 1543-1551, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33784069

RESUMO

Reliable and accurate glucose detection in biological samples is of great importance in clinical diagnosis and medical research. Chemical probes are advantageous in simple operation and flexible design, especially for the development of fluorescent probes. Anthracene-based diboronic acid (P-DBA) has shown potential in glucose probing because of its high sensitivity. However, poor solubility limits its applications in aqueous media. In this work, we systemically modify P-DBA by introducing fluoro (F-), chloro (Cl-), methoxyl (MeO-), or cyano (CN-) substituents. Among these probes, the cyano-substituted probe (CN-DBA) displays the highest glucose-binding constant (6489.5 M-1, 33% MeOH). More importantly, it shows good water solubility in the aqueous solution (0.5% MeOH), with ultrasensitive recognition with glucose (LOD = 1.51 µM) and robust sensing from pH 6.0 to 9.0. Based on these features, the CN-DBA is finally applied to detect glucose in cell lysates and plasma, with satisfactory recovery and precision. These results demonstrate that CN-DBA could serve as an accurate, sensitive fluorescent probe for glucose assays in biological samples.


Assuntos
Corantes Fluorescentes , Glucose , Solubilidade , Água
11.
Lancet Oncol ; 22(3): 351-360, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33581774

RESUMO

BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. FINDINGS: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. INTERPRETATION: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Acrilamidas/administração & dosagem , Adulto , Aminoquinolinas/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/secundário , Capecitabina/administração & dosagem , Feminino , Seguimentos , Humanos , Lapatinib/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
12.
Anal Bioanal Chem ; 413(6): 1533-1540, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33462658

RESUMO

A facile and economic colorimetric strategy was designed for ATP detection by rationally using urease, a pH-responsive molecule, and a metal-mediated switchable DNA probe. By utilizing metal ions as a modulator of urease activity, the concentration of ATP is translated into pH change, which can be readily visualized by naked eye. An unmodified single-stranded DNA probe was designed, which consists of a target binding sequence and two flanked cytosine (C)-rich sequences. This C-rich single-stranded DNA can form a hairpin structure triggered by Ag+ ions via C-Ag+-C base mismatch. Upon introduction of ATP, Ag+-coordinated hairpin DNA structure will be broken and release the included Ag+, thus inhibiting the activity of urease. Conversely, urease can hydrolyze urea and raise pH value of the solution, resulting in the color change of the sensing solution. The proposed assay allows determination of ATP as low as 1.6 nM and shows a satisfactory result in human serum. Because of simple operation and low cost of this method, we believe it has a potential in point-of-care (POC) testing in resource-limited areas. Schematic illustration of pH-responsive colorimetric sensor for ATP detection based on switchable DNA aptamer and metal ion-urease interactions.


Assuntos
Trifosfato de Adenosina/análise , Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais , Colorimetria/métodos , Íons/química , Metais/química , Bioensaio , DNA de Cadeia Simples/química , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Testes Imediatos , Ligação Proteica , Soro/efeitos dos fármacos , Prata/química , Espectrofotometria Ultravioleta , Urease/química
13.
Int J Cancer ; 148(3): 692-701, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32700765

RESUMO

Although receptor status including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) of the primary breast tumors was related to the prognosis of breast cancer patients, little information is yet available on whether patient management and survival are impacted by receptor conversion in breast cancer metastases. Using data from the nation-wide multicenter clinical epidemiology study of advanced breast cancer in China (NCT03047889), we report the situation of retesting ER, PR and HER2 status for breast cancer metastases and evaluate the patient management and prognostic value of receptor conversion. In total, 3295 patients were analyzed and 1583 (48.0%) patients retesting receptor status for metastasis. Discordance in one or more receptors between the primary and the metastatic biopsy was found in 37.7% of women. Patients who remained hormone receptor (HR) positive in their metastases had similar progression-free survival of first-line and second-line treatment compared to patients with HR conversion (P > .05). In multivariate analysis, patients who showed ER conversion from negative to positive had longer disease-free survival (DFS) than patients who remained negative in their metastases (hazard ratio, 2.05; 95% confidence interval [CI], 1.45-2.90; P < .001). Patients with PR remained positive and had longer DFS than patients with PR conversion from negative to positive (hazard ratio, 0.56; 95% CI, 0.38-0.83; P = .004). Patients with PR conversion have shorter overall survival than patients with PR remained positive or negative (P = .016 and P = .041, respectively). Our findings showed that the receptors' conversions were common in metastatic breast cancer, and the conversion impacted the survival.


Assuntos
Neoplasias da Mama/mortalidade , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/metabolismo , Intervalo Livre de Doença , Estudos Epidemiológicos , Feminino , Humanos , Análise Multivariada , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos
14.
Cancer Med ; 10(1): 109-118, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33128299

RESUMO

BACKGROUND: The recommended phase 2 dose (RP2D) of pamiparib, an investigational PARP1/2 inhibitor, was established as 60 mg twice daily (BID) in a first-in-human (FIH) study (NCT02361723). METHODS: Chinese patients with advanced non-mucinous high-grade ovarian cancer (HGOC) or triple-negative breast cancer (TNBC) whose disease either progressed despite standard therapy, or for which there is no standard therapy were enrolled in the dose-escalation (DE) portion of a phase 1/2 study (NCT03333915). The primary endpoint was safety/tolerability; secondary objectives were pharmacokinetics and antitumor activity. BRCA1/2 mutation status was retrospectively evaluated. RESULTS: Nine HGOC and six TNBC patients (N = 15; n = 4, 20 mg; n = 4, 40 mg; n = 7, 60 mg) were enrolled; as of 30 September 2019, one HGOC patient remained on treatment. Seven patients (n = 5, HGOC; n = 2, TNBC) had germline BRCA1/2 mutation (gBRCAmut ); all HGOC patients were resistant/refractory to platinum. Asthenia and nausea (n = 12 each) were the most common treatment-related adverse events (TRAEs). Decreased hemoglobin was the most common grade 3 TRAE (n = 3); no grade ≥4 AEs were observed. No dose-limiting toxicities (DLTs) were reported. Pamiparib plasma exposure was similar to exposure observed in the FIH study after a single-dose administration, albeit slightly higher at steady state. Among 13 RECIST-evaluable patients, two with HGOC (gBRCAmut , n = 1) achieved a confirmed partial response and six with HGOC (gBRCAmut , n = 4) achieved stable disease; all TNBC RECIST-evaluable patients (n = 5) reported progressive disease. CONCLUSIONS: Pamiparib was generally well tolerated in Chinese patients, with durable responses observed in patients with HGOC. Based on these results, pamiparib 60 mg BID was confirmed as the RP2D.

15.
J Control Release ; 330: 483-492, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33383096

RESUMO

As a photosensitizer with effective photothermal (PTT) and photodynamic (PDT) response, IR780 has been widely explored as promising cancer phototheranostic molecule. However, the systematic administration of IR780 usually suffers from poor water solubility and low photostability, so that it cannot be administrated by parenteral route. In this study, we design a tetrahedral DNA (Td)-based nanosystem to load IR780 (IR780@Td) via electrostatic interaction and π-π stacking. After encapsulation, the water solubility and photostability of IR780 have been greatly improved, and the IR780@Td shows an appropriate nanoformulated size (224 nm) to facilitate hyperthermia-mediated tumor targeting by EPR effect. The nanostructure of Td is proved to be crucial for the proper size and good stability of IR780@Td nanoformulation for in vivo application. The in vitro and ex vivo PTT/PDT efficiencies of IR780 are improved in IR780@Td group. In the tumor-bearing mice, the accumulation of IR780 in tumor site is significantly high in IR780@Td group. Under near-infrared laser irradiation, the intravenous administration of IR780@Td promotes the tumor imaging and enhances anti-tumor effect than IR780 treatment. In summary, the proposed strategy shows promising effect in facilitating intravenous injection of IR780 and enhancing the phototheranostic efficacy for cancer treatment.


Assuntos
Hipertermia Induzida , Nanopartículas , Nanoestruturas , Neoplasias , Fotoquimioterapia , Animais , Linhagem Celular Tumoral , DNA , Indóis , Camundongos , Neoplasias/tratamento farmacológico
16.
Front Immunol ; 11: 2063, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013872

RESUMO

Background: Cases of excessive neutrophil counts in the blood in severe coronavirus disease (COVID-19) patients have drawn significant attention. Neutrophil infiltration was also noted on the pathological findings from autopsies. It is urgent to clarify the pathogenesis of neutrophils leading to severe pneumonia in COVID-19. Methods: A retrospective analysis was performed on 55 COVID-19 patients classified as mild (n = 22), moderate (n = 25), and severe (n = 8) according to the Guidelines released by the National Health Commission of China. Trends relating leukocyte counts and lungs examined by chest CT scan were quantified by Bayesian inference. Transcriptional signatures of host immune cells of four COVID19 patients were analyzed by RNA sequencing of lung specimens and BALF. Results: Neutrophilia occurred in 6 of 8 severe patients at 7-19 days after symptom onset, coinciding with lesion progression. Increasing neutrophil counts paralleled lesion CT values (slope: 0.8 and 0.3-1.2), reflecting neutrophilia-induced lung injury in severe patients. Transcriptome analysis revealed that neutrophil activation was correlated with 17 neutrophil extracellular trap (NET)-associated genes in COVID-19 patients, which was related to innate immunity and interacted with T/NK/B cells, as supported by a protein-protein interaction network analysis. Conclusion: Excessive neutrophils and associated NETs could explain the pathogenesis of lung injury in COVID-19 pneumonia.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Armadilhas Extracelulares/genética , Ativação de Neutrófilo/genética , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Teorema de Bayes , COVID-19 , Infecções por Coronavirus/virologia , Feminino , Humanos , Contagem de Leucócitos , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Masculino , Pessoa de Meia-Idade , Infiltração de Neutrófilos/imunologia , Pandemias , Pneumonia Viral/virologia , Mapas de Interação de Proteínas/imunologia , RNA Viral/genética , Estudos Retrospectivos , SARS-CoV-2 , Transcriptoma
17.
Sci Rep ; 10(1): 18132, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093581

RESUMO

Stage IV breast cancer is metastatic breast cancer (MBC). Because real-world data are lacking in China, our research attempts to explore the effect of locoregional surgery on the prognosis of patients with MBC. A total of 987 patients from 10 hospitals and 2 databases in East China (2004-2018) were included in this study. Overall, 47% of patients underwent locoregional surgery, and 53% did not. Surgeons tended to perform surgery on patients with small tumours (T1/T2), positive hormone receptor (HR) markers, and metastatic sites confined to a single organ and non-visceral sites (bone only/others) (each p < 0.05). Kaplan-Meier survival curves and the log-rank test showed that median survival was longer for patients who had locoregional surgery than for those who did not (45.00 vs. 28.00 months; p < 0.001). Patients who underwent surgery after systemic treatment had better survival than those who underwent surgery immediately (p < 0.001). In most subgroups, overall survival (OS) was significantly longer in the surgery group than in the no-surgery group (each p < 0.05), except for brain metastases and triple negative breast cancer. Therefore, we concluded that locoregional surgery for the primary tumour in MBC patients was associated with a marked reduction in risk of dying except for patients with brain metastases or triple-negative subtype.


Assuntos
Neoplasias Ósseas/cirurgia , Neoplasias da Mama/cirurgia , Recidiva Local de Neoplasia/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , China , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
18.
Front Pharmacol ; 11: 577150, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013420

RESUMO

Lapatinib, targeting the human epidermal growth factor receptor family members HER1 and HER2, has been approved by the US Food and Drug Administration for use in metastatic HER2-positive breast cancer. However, resistance to lapatinib remains a common challenge to HER2-positive metastatic breast cancer. Until now, the molecular mechanisms of acquired resistance to lapatinib (ALR) have remained unclear. With no definite biomarkers currently known, we aimed to screen for key biomarkers in ALR. In this research, we identified 55 differentially expressed genes (DEGs, 20 upregulated, 35 downregulated) through bioinformatic analysis using microarray datasets GSE16179, GSE38376, and GSE51889 from the Gene Expression Omnibus (GEO) database. The related gene function was explored using the Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The protein-protein interaction (PPI) network was constructed with the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. The functional enrichment of the DEGs was analyzed, including negative regulation of the B cell apoptotic process, DNA replication, solute:proton symporter activity, synthesis, and degradation of ketone bodies, and metal sequestration by antimicrobial proteins. Analysis of seven hub genes revealed their concentration mainly in DNA replication and cell cycle. Survival analysis revealed that MCM10 and SPC24 may be related with poor prognosis in patients with ALR. Meanwhile, the prediction model of lapatinib sensitivity was constructed, and emerging role of the model was further analyzed using several webtools. In conclusion, hub genes are involved in the complex mechanisms underlying ALR in breast cancer and provide favorable support for treatment of ALR in future.

19.
J Cancer ; 11(22): 6695-6699, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33046990

RESUMO

Purpose: The aberrant of fibroblast growth factors and their receptors (FGF/FGFR) is an emerging target in the treatment of solid tumors. This study aimed to explore the landscape of FGF/FGFR alterations in a large cohort of cancer patients. Material and Methods: The formalin-fixed paraffin-embedded specimens of cancer patients who have underwent next-generation sequencing (NGS) from 2017 to 2019 in 3DMed Clinical Laboratory Inc. were included in this study. Findings: Of 12,372 Chinese cancer patients with more than 20 tumor types (60% male, median age, 58.0 [IQR, 49.0-66.0]), genomic alterations in FGF, FGFR, and both were observed in 895 (7.2%), 862 (7.0%), and 186 (1.5%) patients, respectively. The highest prevalence of FGF/FGFR mutations fell in esophagus cancer (61.6%, 98/159) and urinary tract cancer (52.7%, 145/275). The most common pathway-level mutations were FGFR single nucleotide variants (635, 5.1%) and FGF amplifications (628, 5.1%). The microsatellite instability status was negatively associated with amplifications (p=0.0017). Conclusion: FGF/FGFR alterations were widely occurred in cancer patients, and the mutational landscape may contribute to the further study design and development of FGF/FGFR inhibitors.

20.
Front Cell Dev Biol ; 8: 832, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32984327

RESUMO

Differential regulation of gene transcription contributes to cancer metastasis. We investigated the involvement of a Rho GTPase (RhoJ) in breast cancer metastasis focusing on the mechanism underlying RhoJ trans-activation by pro-metastatic cues. We report that expression of RhoJ was up-regulated in malignant breast cancer cells compared to more benign ones. Higher RhoJ expression was also detected in human breast cancer biopsy specimens of advanced stages. RhoJ depletion attenuated breast cancer cell migration and invasion in vitro and metastasis in vivo. The pro-metastatic stimulus TGF-ß activated RhoJ via megakaryocytic leukemia 1 (MKL1). MKL1 interacted with and was recruited by ETS-related gene 1 (ERG1) to the RhoJ promoter to activate transcription. In conclusion, our data delineate a novel transcriptional pathway that contributes to breast cancer metastasis. Targeting the ERG1-MKL1-RhoJ axis may be considered as a reasonable approach to treat malignant breast cancer.

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