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1.
Reprod Biol Endocrinol ; 19(1): 144, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526015

RESUMO

In mammals, germline development undergoes dramatic morphological and molecular changes and is epigenetically subject to intricate yet exquisite regulation. Which epigenetic players and how they participate in the germline developmental process are not fully characterized. Spin1 is a multifunctional epigenetic protein reader that has been shown to recognize H3 "K4me3-R8me2a" histone marks, and more recently the non-canonical bivalent H3 "K4me3-K9me3/2" marks as well. As a robust Spin1-interacting cofactor, Spindoc has been identified to enhance the binding of Spin1 to its substrate histone marks, thereby modulating the downstream signaling; However, the physiological role of Spindoc in germline development is unknown. We generated two Spindoc knockout mouse models through CRISPR/Cas9 strategy, which revealed that Spindoc is specifically required for haploid spermatid development, but not essential for meiotic divisions in spermatocytes. This study unveiled a new epigenetic player that participates in haploid germline development.

2.
Nanoscale Horiz ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542134

RESUMO

Treating cancer with high efficacy while eliminating side effects has been the holy grail of cancer research. The challenge, however, arises from the similarity in molecular traits of cancer cells and normal cells because truly specific cancer biomarkers are extremely scarce if not entirely unavailable. Often, biomarkers serving as the therapeutic targets are present on both healthy cells and cancers, but at different levels, causing not only off-target side effects but also on-target side effects. This work has reported a new concept of cancer treatment, spatial confinement of cells to inhibit cell migration and invasion, which directly addresses the defining trait of cancer on the cellular level, unchecked division. Using large sized graphene oxide (LS-GO), cell surfaces can be patched. Unlike conventional chemotherapy, this spatial confinement does not affect the viability of non-dividing cells but significantly inhibits tumor cell migration and invasion in vitro and in vivo. This new concept has the potential to become a general therapeutic for many cancer types with reduced side effects.

3.
J Environ Manage ; 298: 113543, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34392095

RESUMO

Algae based wastewater treatment has been considered as the most promising win-win strategy for nutrients removal and biomass accumulation. However, the poor linking between traditional wastewater treatment and algal cultivation limits the achievement of this goal. In this study, a novel combination of Fenton oxidation and algal cultivation (CFOAC) system was investigated for the treatment of chicken farm flushing wastewater (CFFW). Fenton oxidation (FO) was adopted to reduce the excessive ammonia nitrogen, which might inhibit the algal growth. The results showed that single FO pretreatment removed 70.5 %, 96.7 %, 86.1 %, and 96.2 % of TN, TAN, TP, and COD, respectively. The highest biomass (235.8 mg/L/d) and lipid (77.3 mg/L/d) productivities were achieved on optimized CFOAC system after 7 days batch cultivation. Accordingly, the nutrients removal efficiencies increased to almost 100 %. Further fatty acid profile analysis showed that algae grown on optimal CFOAC system accumulated a high level of total lipids (32.8 %) with C16-C18 fatty acid as the most abundant compositions (accounting for over 60.6 %), which were propitious to biodiesel production. In addition, this CFOAC system was magnified from 1 L flask to 50 L horizontal pipe photobioreactor (HPPB) in semi-continuously culture under optimal conditions. The average biomass and lipid productivities were 995.7 mg/L/d and 320.6 mg/L/d, respectively, when cultured at 6 days hydraulic retention time with 1/3 substitution every two days. These findings proved that the novel CFOAC system is efficient in nutrients removal, algal cultivation, and biomass production for advanced treatment of CFFW.


Assuntos
Microalgas , Águas Residuárias , Animais , Biocombustíveis , Biomassa , Galinhas , Fazendas , Nitrogênio/análise , Nutrientes
4.
ACS Appl Mater Interfaces ; 13(33): 39719-39729, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34392680

RESUMO

In this work, cucurbiturils (CBs), a class of macrocyclic supramolecules, were observed to have an interesting peroxidase-like activity, which is metal-free, substrate-specific, thermophilic, acidophilic, and insensitive to ionic strength. By coating CBs on enzyme-encapsulated zeolitic imidazolate framework-8 (ZIF-8), a composite nanozyme was constructed, which retains the catalytic ability of CBs and enzymes and makes them cascade. On addition of the substrate, i.e., the detection target, a highly efficient cascade catalysis can be launched in all the spatial directions to generate sensitive and visible signals. Convenient detection of glucose and cholesterol as models is thereby achieved. More importantly, we have also successfully constructed a composite nanozyme-based sensor array (6 × 8 wells) and thereby achieved simultaneous colorimetric analysis of multiple samples. The concept and successful practice of the construction of the unique core-shell supramolecule/biomolecule@nanomaterial architecture provide the possibility to fabricate next-generation multifunctional materials and create new applications by integrating their unique functions.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Nanocompostos/química , Peroxidases/química , Zeolitas/química , Técnicas Biossensoriais , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Catálise , Colorimetria , Corantes Fluorescentes/química , Glucose Oxidase/química , Glucose Oxidase/metabolismo , Peróxido de Hidrogênio/química , Imidazóis/metabolismo , Simulação de Acoplamento Molecular , Oxirredução , Peroxidases/metabolismo , Impressão Tridimensional
5.
J Cell Mol Med ; 25(19): 9199-9213, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34431227

RESUMO

Long non-coding RNA (lncRNA) colon cancer associated transcript 1 (CCAT1) has been identified as an oncogene in many cancers, but its role in lung adenocarcinoma (LUAD) remains to be further investigated. We identified the upregulation of CCAT1 in LUAD tissues and LUAD cells. Through RNA pull-down and mass spectrometry analysis, we obtained the interacting proteins with CCAT1 and discovered their functional relation with 'signal transduction', 'energy pathways' and 'metabolism' and revealed the potential of CCAT1 on fatty acid (FA) metabolism. For mechanism exploration, we uncovered the mediation of CCAT1 on the translocation of fatty acid binding protein 5 (FABP5) into nucleus by confirming their interaction and localization. Also, CCAT1 was discovered to promote the formation of the transcription complex by RXR and PPARγ so as to activate the transcription of CD36, PDK1 and VEGFA. Moreover, we found that CCAT1 regulated the activity of AKT by promoting the ubiquitination of FKBP51 through binding with USP49. Subsequently, cell function assays revealed the enhancement of CCAT1 on LUAD cell proliferation and angiogenesis in vitro and in vivo. Collectively, CCAT1 regulated cell proliferation and angiogenesis through regulating FA metabolism in LUAD, providing a novel target for LUAD treatment.

6.
Toxicol Ind Health ; 37(9): 513-519, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34342256

RESUMO

Chlorine is an irritant gas that is widely used in water purification. Several previous reports had reported accidents of inhalation injuries at swimming pools. However, there have been limited data on the detection of on-site chlorine concentration. This study aims to report a chlorine leakage accident at a swimming pool caused by improper disinfection operations. Calculation using the gas diffusion simulation software showed that the on-site chlorine concentration was 221.45 ppm. When the accident occurred, there were 92 individuals at the swimming pool and the gym, among which 61 were referred to the emergency department of five different hospitals for feeling ill. Among them, 22 patients underwent chest high-resolution computed tomography scans in our hospital. According to the findings, 4 (18.2%) patients had peribronchitis, 3 (13.6%) had tracheobronchitis, 4 (18.2%) had pneumonia, 4 (18.2%) had interstitial pulmonary edema, and 3 (13.6%) had alveolar pulmonary edema. The symptoms of 22 patients who visited our hospital significantly improved after comprehensive treatment. Three months after the accident, 8 of 17 patients presented obstructive ventilation defects or small airway dysfunction. The accidental exposure to chlorine may induce acute poisoning with various respiratory injuries and prolonged lung dysfunction.

7.
Curr Oncol ; 28(4): 3115-3123, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34436038

RESUMO

To compare the outcomes of patients who had deep-lobe parotid gland pleomorphic adenomas (PAs) that extended into the parapharyngeal space after surgical treatment, using a transoral approach or an external approach. One hundred and twelve eligible patients, with deep-lobe parotid gland PAs, were enrolled in this retrospective study. The surgical outcomes were compared for patients who received a transoral approach and an external approach, using 1:1 propensity score matching (PSM). The outcome measures were recurrence rate, facial nerve deficit, Frey's syndrome, and hospitalization time. The median follow-up time was 4.8 years. After PSM, the transoral approach and external approach groups had no statistically significant difference in recurrence (10.3% vs. 3.4%; p = 0.201). The transoral approach group had no facial nerve deficit, but 5 of 29 patients (17.2%) in the external approach group had transient facial nerve paralysis (p = 0.052). The external approach group had a longer hospitalization time than the transoral approach group (5 vs. 4 days, p = 0.0017). The use of a transoral surgical approach to treat patients with deep-lobe parotid gland PAs led to low recurrence, shorter hospitalization times, and good functional and cosmetic outcomes.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34334385

RESUMO

BACKGROUND: Acoustic Radiation Force Impulse (ARFI), Fibrosis-4(FIB-4) and Aspartate transaminase to platelet ratio index (APRI) are valuable non-invasive methods to evaluate fibrosis in hepatitis virus. Yet, they are rarely used in Wilson's disease. OBJECTIVE: Evaluate the diagnostic efficacy of ARFI, FIB-4, APRI, combined detection in cirrhosis with WD, and speculate the optimal high, low cutoff. METHODS: This retrospective study was authorized by hospital ethics Committee (number:2021MCZQ02). 102 patients with WD completed ARFI and laboratory examination on the same day. The intraclass correlation coeffcient (ICC) of ARFI among three sonographers was 0.896 (95%CI:0.859-0.925, p = 0.000). The stage of liver involvement was classified into 5 categories according to clinical manifestations, laboratory examination, and liver morphologic characteristics: I, normal; II, biochemical abnormal only; III, abnormal liver morphologic features without sighs of cirrhosis; IV, clinical and imaging sighs of compensateded cirrhosis (Child-Pugh A); V, decompensated cirrhosis (Child-Pugh B and C). This stage system served as the reference standard. The diagnostic efficacy was analyzed by Logistic regression, ROC curve. The optimal low cut-off with high sensitivity (SE) and low negative likelihood ratio (NLR) and high cut-off with high specificity (SP) and positive likelihood ratio (PLR) were derived. RESULTS: The diagnostic value of ARFI (0.85, 95%CI:0.77-0.92, p = 0.000) in distiguishing cirrhosis with WD was higher than FIB-4 (0.59, 95%CI: 0.47-0.70, p = 0.127), APRI (0.70, 95%CI: 0.59-0.81, p = 0.000). The low, high cut-off of ARFI for excluding, diagnosing cirrhosis with WD was 1.47 m/s(SE: 98%, NLR:0.09), 2.11 m/s(SP:98%, PLR:27.4), 37 (36%) patients could be spared a liver biopsy. When ARFI was 1.47∼2.11 m/s, liver biopsy was recommended. After combined with ARFI, the AUROC of FIB-4, APRI were increased respectively (p <  0.001), there were not different between ARFI and combined detection(p >  0.05). CONCLUSION: ARFI could replace some unnecessary liver biopsy according to high diagnostic efficacy for identifying cirrhosis of WD. The combined detection can also be used as an important model to predict cirrhosis in WD.

9.
Cardiovasc Intervent Radiol ; 44(10): 1597-1608, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34240232

RESUMO

OBJECTIVES: Based on an artificial intelligence approach, this study attempted to establish prognostic models to predict 3-month overt hepatic encephalopathy (OHE) occurrence, 1-year mortality, and liver dysfunction for cirrhotic patients with acute variceal bleeding (AVB) treated with early transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS: This retrospective study included patients treated with early TIPS between January 2016 and November 2019. Independent risk factors associated with occurrence of OHE within 3 months, 1-year mortality, and liver dysfunction after early TIPS were identified using univariate and multivariate logistic analyses. Artificial neural network (ANN) models and prognostic nomograms based on the independent risk factors were established and validated internally. RESULTS: A total of 207 patients were included, with 33 (15.9%) experienced OHE within 3 months after TIPS creation. The albumin-bilirubin grade (P = 0.015), age (≤ 65, > 65 years) (P < 0.001), gender (P = 0.002), and alcoholic cirrhosis (P = 0.013) was identified as independent risk factors associated with 3-month OHE. Presence of portal vein thrombosis (P = 0.034) and model for end-stage liver disease score (P = 0.063) were identified as independent risk factors associated with 1-year mortality. The platelet-albumin-bilirubin grade (P = 0.041) and a history of hepatic encephalopathy (P = 0.018) were identified as independent risk factors associated with liver dysfunction after TIPS creation. Three ANN models and three nomograms were then established and validated with high accuracy. CONCLUSIONS: The ANN and nomogram models have potential to accurately predict early occurrence of OHE, mortality, and liver dysfunction after early TIPS creation for cirrhotic patients with AVB.

10.
Cancer Invest ; 39(9): 734-740, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34232825

RESUMO

BACKGROUND: The purpose of this study was to compare survival outcomes in patients with perineural invasion (PNI)-positive laryngeal squamous cell carcinoma (LSCC) and patients with PNI-negative LSCC. METHODS: A total of 1,272 patients with LSCC, diagnosed between 2008 and 2017, were included in this study. LSCC Patients with and without PNI were matched based on possible confounding factors. Survival analysis was performed using Kaplan-Meier estimates and the Cox proportional hazards model. RESULTS: Of the 1,272 LSCC patients, 118 (9.28%) were positive for PNI. Compared to PNI-negative patients, PNI-positive LSCC patients had significantly worse overall survival (OS) (p = 0.017), disease-specific survival (DSS) (p = 0.034) and recurrence-free survival (RFS) (p = 0.002). After pair matching, cohorts consisted of 118 patients in the PNI-positive group and 118 in the PNI-negative group. Significantly increased risk of OS (HR, 2.17; 95% confidence interval [CI], 1.29-3.61, p = 0.003), DSS (HR, 2.07; 95% CI, 1.32-3.24, p = 0.004) and RFS (HR, 2.65; 95% CI, 1.59-4.40, p < 0.001) was observed after adjustment for prognostic variables. CONCLUSIONS: Patients with PNI-positive LSCC have significantly worse survival outcomes compared to patients with PNI-negative LSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Laríngeas/patologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Nervos Periféricos/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/cirurgia , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prognóstico , Modelos de Riscos Proporcionais
11.
J Cancer Res Clin Oncol ; 147(10): 2935-2944, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34254208

RESUMO

PURPOSE: BRCA1/2 screening for all triple-negative breast cancer (TNBC) patients younger than 60 years may still be an economic burden in China. Further evidences that include incidence and outcome of BRCA1/2 pathogenic variants (PV) screened based on younger age or family history (FH) are worth discussing for improving the cost-effectiveness of BRCA1/2 testing in Chinese TNBC. We aimed to investigate the prevalence of germline and tumor BRCA1/2 PV based on age screening in Chinese TNBC patients. METHODS: Paired blood and tumor DNA from 124 unselected Chinese TNBC patients with less than or equal to 55 years were collected and analyzed for BRCA1/2 PV. Clinicopathological characteristics including age at diagnosis, FH and follow-up data were collected for further analysis. RESULTS: The entire frequency of germline and tumor BRCA1/2 PV was 21.0 and 25%, respectively. Among them, 20 (16.1%) germline and 5 (4.0%) somatic BRCA1/2 single-nucleotide variant/insertion/deletions were found by NGS testing, 6 (4.8%) BRCA1 large genomic rearrangements were detected in blood DNA by MPLA. There was significant correlation between FH of HBOC and germline BRCA1/2 PVs among these patients. Patients with tumor BRCA1/2 PVs had significant improvements than non-carriers in PFS (p = 0.047). No significant impacts were found between various mutation status in OS outcomes. No significant differences were found between BRCA1 or BRCA2 and non-carriers in PFS or OS. CONCLUSION: There is a high incidence of germline and tumor BRCA1/2 PVs in Chinese TNBC patients with less than or equal to 55 years old. Tumor BRCA1/2 PV carriers showed an improved survival outcome. Our results suggest that BRCA1/2 PVs testing addressed within each specific clinical scenario could be more cost-effective for patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias de Mama Triplo Negativas/patologia , Adolescente , Adulto , China/epidemiologia , Feminino , Seguimentos , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/genética , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-34293120

RESUMO

OBJECTIVES: The aim of this study was to present surgical techniques and evaluate outcomes of a sternocleidomastoid muscle (SCM) myoperiosteal flap used for the reconstruction of tracheal or laryngotracheal defects after the radical resection of invasive thyroid carcinoma. METHODS: A retrospective study was performed for patients at Peking Union Medical College Hospital from January 2008 to December 2018 of papillary thyroid carcinoma with tracheal or laryngotracheal invasion. Patients were enrolled only when they received window resection and reconstruction via an SCM myoperiosteal flap. The primary outcome was a stable airway, and the secondary outcome was survival. RESULTS: A total of 15 invasive thyroid carcinoma patients were enrolled in this study. Laryngotracheal and tracheal reconstruction were performed in 11 and 4 patients respectively, with a median vertical defect of 3.5 cm (3.0, 4.5). A stable airway was achieved in 14 patients postoperatively. One patient experienced tracheal stenosis and received a second operation of tracheal sleeve resection and end-to-end anastomosis 105 days after the first operation. Tracheostomy was conducted in 5 out of 15 patients in whom the vertical defects were larger than 4 cm, and the tubes were extubated after a median time of 56 days (32, 84). The median observation time was 55 months (48, 86), and all 15 patients achieved a stable airway and showed no evidence of local recurrence at the end of follow-up. CONCLUSIONS: For thyroid carcinoma with tracheal or laryngotracheal invasions, window resection with the SCM myoperiosteal flap reconstruction presented positive results in terms of a stable airway as well as oncological outcomes. The SCM myoperiosteal flap can be an appropriate reconstruction strategy, especially when the defects reach the thyroid cartilage.

13.
J Cancer Res Ther ; 17(3): 613-618, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34269289

RESUMO

Pancreatic cancer (PC) is a lethal disease with extremely high mortality. Although surgical resection is the optimal therapeutic approach for PC, about 30%-40% of those patients are not candidates for surgical resection when diagnosed. Chemotherapy and radiotherapy also could not claim a desirable effect on PC. The application of interventional radiology approaches is limited by unavoidable damage to the surrounding vessels or organs. By the superiority of mechanism and technology, IRE could ablate the tumor by creating irreversible pores on the membrane of PC cells with other tissues like vessels and pancreatic ducts untouched. This consensus gathers the theoretical basis and clinical experience from multiple Chinese medical centers, to provide the application principles and experience from Chinese experts in the IRE field.

14.
J Cancer Res Ther ; 17(3): 638-643, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34269293

RESUMO

Settings and Design: The aim was to study the changes in thyroid antibody and T lymphocyte subsets after radiofrequency ablation (RFA) of thyroid nodules in patients with autoimmune thyroiditis. Subjects and Methods: Patients (n = 135) with autoimmune thyroiditis and thyroid nodules were treated by RFA. The indices of thyroid function and thyroid antibody and T lymphocyte subsets were examined preoperation and on the 1st day and the 1st month after ablation. Any complications were recorded. Statistical Analysis: The software SPSS 17.0.0 (version: 2008-8-23) running under Windows 8 was used for statistical analysis. The measurement data were expressed as x ± s, with P < 0.01 indicating a significant difference in the statistical data. Results: Levels of free triiodothyronine, free thyroxine, and thyroid-stimulating hormone were in the normal range before ablation, and no significant changes occurred on the 1st day or in the 1st month after ablation. The change in the percentage of CD8+T cells and the absolute value of B cells were not statistically significant (P > 0.01), and the values were in the normal range. Compared with values recorded preoperation, the value of TG-Ab, TPO-Ab, CD4+/CD8+, the percentage of CD4+T cells, the absolute values of lymphocytes, T cells, CD4+T cells, and CD8+T cells decreased significantly at the 1st day after ablation (P < 0.01) and then recovered to preoperative levels during the first 30 days after ablation (P > 0.01). Within 1 month after ablation, none of the patients had complications such as active bleeding, infection, recurrent laryngeal nerve injury, parathyroid gland injury, skin scald, and so on. Conclusions: After RFA of thyroid nodules in patients with autoimmune thyroiditis, thyroid function is not affected and no serious complications occurred. TG-Ab and TPO-Ab levels can be significantly decreased, and the distribution of T lymphocyte subsets can be changed in the short term after ablation.

15.
Materials (Basel) ; 14(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34300848

RESUMO

Difenacoum (DIF) is one of the most widely used anticoagulant rodenticides. However, accidental or intentional ingestion of DIF seriously threatens humans and other non-target species. Therefore, a rapid and sensitive detection method to quantify DIF is urgently needed. In this study, one anti-DIF nanobody (Nb) was assembled on the surface of a gold interdigitated microelectrode (IDME) using an Au-S bond to fabricate a bioimpedance sensor. To improve the immobilization amount of Nbs on the electrode, a polycrystalline gold IDME was prepared to provide a larger surface and better biocompatibility. Thus, a novel and ultrasensitive bioimpedance sensor based on electrochemical impedance spectroscopy (EIS) was designed for the determination of DIF, and it displayed good reproducibility and stability in human serum. The proposed bioimpedance sensor displayed a wide working range, between 0.1-1000 pg/mL, with a limit of detection (LOD) of 0.1 pg/mL of DIF. This method exhibited excellent performance, good sensitivity, and reproducibility and achieved the highest sensitivity of all currently existing methods used to quantify DIF. The highly sensitive DIF detection of this proposed bioimpedance sensor indicates its potential as an efficacious approach for DIF monitoring in human serum with high accuracy and precision.

16.
Cancer Commun (Lond) ; 41(9): 889-903, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34184418

RESUMO

BACKGROUND: Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC). METHODS: Stage IIIB-IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4-6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127). RESULTS: Between December 15th , 2017, and May 15th , 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th , 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1-6) and median duration of treatment of 3.0 (range 0.0-5.1) months. ORR of response-evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80-1.04, within the prespecified equivalence margin of 0.75-1.33). Up to May 15th , 2020, with a median follow-up of 13.6 (range 0.8-28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1-year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups. CONCLUSIONS: LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non-squamous NSCLC patients in the first-line setting.

17.
Cardiovasc Intervent Radiol ; 44(10): 1570-1578, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34117503

RESUMO

PURPOSE: To compare the safety and efficacy of integrated iodine-125 (I-125) seed implantation (sequential implantation of helical I-125 seed implant into the main portal vein and of I-125 seeds into the branch tumor thrombus directly forming main portal vein tumor thrombus (MPVTT)) combined with transarterial chemoembolization (TACE) versus TACE alone for hepatocellular carcinoma (HCC) with MPVTT. MATERIALS AND METHODS: From December 2016 to January 2020, 46 HCC patients with MPVTT were analyzed. In the combination group, 21 patients received helical I-125 seed implantation in the main portal vein through a patent small portal vein branch and TACE in a single session. After 7-10 days, I-125 seeds were implanted percutaneously into the branch tumor thrombus directly forming MPVTT. In the TACE group, 25 patients received TACE alone. Thereafter, TACE was repeated as needed in both groups. Adverse events, tumor response, and overall survival (OS) of the two groups were compared. RESULTS: No adverse events grade ≥ 3 were observed in either group. The optimal objective response rate and disease control rate for MPVTT in the combination group and TACE group were 52.4% versus 4.0% (P < 0.001) and 85.7% versus 32.0% (P < 0.001), respectively. Median OS in the combination group (9.8 months) was longer than in the TACE group (5.2 months) (P = 0.024). Multivariate analysis revealed that, compared with the TACE group, the mortality risk in the combination group significantly decreased (hazard ratio: 0.444; P = 0.020). CONCLUSION: Integrated I-125 seed implantation combined with TACE is a safe and effective treatment for HCC with MPVTT. LEVEL OF EVIDENCE: Level 3, Non-randomized controlled cohort/follow-up study.

18.
Small ; 17(29): e2101224, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34145748

RESUMO

The delivery of mRNA to manipulate protein expression has attracted widespread attention, since that mRNA overcomes the problem of infection and mutation risks in transgenes and can work as drugs for the treatment of diseases. Although there are currently some vehicles that deliver mRNA into cells, they have not yet reached a good balance in terms of expression efficiency and biocompatibility. Here, a DNA nano-hydrogel system for mRNA delivery is developed. The nano-hydrogel is all composed of DNA except the target mRNA, so it has superior biocompatibility compared with those chemical vehicles. In parallel, the nano-hydrogel can be compacted into a nanosphere under the crosslinking by well-designed "X"-shaped DNA scaffolds and DNA linkers, facilitating the delivery into cells through endocytosis. In addition, smart intracellular release of the mRNA is achieved by incorporating a pH-responsive i-motif structure into the nano-hydrogel. Thus, taking the efficient delivery and release together, mRNA can be translated into the corresponding protein with a high efficiency, which is comparable to that of the commercial liposome but with a much better biocompatibility. Due to the excellent biocompatibility and efficiency, this nano-hydrogel system is expected to become a competitive alternative for delivering functional mRNA in vivo.


Assuntos
DNA , Hidrogéis , Sistemas de Liberação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , RNA Mensageiro/genética
19.
Anal Chem ; 93(24): 8414-8422, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34114453

RESUMO

Sensitive, accurate, and nondestructive probing of endogenous messenger RNA (mRNA) in living cells places extremely high demands on nanocarriers and probes and is still a challenge. In the present study, we describe a target-triggered self-assembled DNA tree for amplified analysis of mRNA in intact living cells. The probes assembled into a DNA tree are transported into cells by exosomes, which is beneficial for reducing cell damage and realizing nondestructive analysis. The probes are l-configured single-stranded DNAs (LDNAs) that can resist the degradation of exonuclease and endonuclease, thus laying the foundation for accurate analysis. Under the induction of the target mRNA, the probes in the cells assemble into a small plantlet and eventually grow into a tree after a few rounds of self-cycling, achieving the exponential amplification of fluorescence signals. Compared with the signal amplification based on one-dimensional DNA trunk self-assembly, the three-dimensional DNA tree shows an excellent sensitivity both ex situ and in situ. In this way, favorable sensitivity, accuracy, and nondestructive analysis are integrated into one system. This DNA tree expands the analysis platform for analyzing more biomarkers on a genetic level in an intracellular, nondestructive, and hypersensitive manner and holds great potential in clinical diagnostic and research applications.


Assuntos
Exossomos , DNA/genética , Sondas de DNA , DNA de Cadeia Simples , Exossomos/genética , RNA Mensageiro/genética , Árvores
20.
J Thorac Oncol ; 16(9): 1533-1546, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34033974

RESUMO

INTRODUCTION: Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. METHODS: Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. RESULTS: A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation. CONCLUSIONS: Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL. TRIAL REGISTRATION: NCT02824458.


Assuntos
Neoplasias Pulmonares , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica , Intervalo Livre de Doença , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas , Quinazolinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular
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