Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 253
Filtrar
1.
Neuroimage ; 211: 116597, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32018004

RESUMO

Ultrasound-mediated neuromodulation is emerging as a key technology for targeted noninvasive brain stimulation, but key insights into its effects and dose-response characteristics are still missing. The purpose of this study is to systematically evaluate the effect of low-intensity transcranial ultrasound stimulation (TUS) on complementary aspects of cerebral hemodynamic. We simultaneously record the EMG signal, local field potential (LFP) and cortical blood flow (CBF) using electrophysiological recording and laser speckle contrast imaging under ultrasound stimulation to simultaneously monitor motor responses, neural activities and hemodynamic changes during the application of low-intensity TUS in mouse motor cortex, using excitation pulses which caused whisker and tail movement. Our experimental results demonstrate interdependent TUS-induced motor, neural activity and hemodynamic responses that peak approximately 0.55s, 1.05s and 2.5s after TUS onset, respectively, and show a linear coupling relationship between their respective varying response amplitudes to repeated stimuli. We also found monotonic dose-response parametric relations of the CBF peak value increase as a function of stimulation intensity and duration, while stimulus duty-cycle had only a weak effect on peak responses. These findings demonstrate that TUS induces a change in cortical hemodynamics and LSCI provide a high temporal resolution view of these changes.

2.
J Thorac Oncol ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32036071

RESUMO

BACKGROUND: Programmed death receptor-1 (PD-1) inhibitors have shown efficacy in first line treatment of non-small cell lung cancer (NSCLC), however, evidence of PD-1 inhibitor as neoadjuvant treatment is limited. This is a phase 1b study to evaluate the safety and outcome of PD-1 inhibitor in neoadjuvant setting. METHODS: Treatment-naïve patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1/22). Surgery was performed between day 29-43. PET-CT was obtained at baseline and prior to surgery. Primary endpoint was safety. Efficacy endpoints included rate of major pathologic response (MPR) and objective response rate (ORR). PD-L1 expression was also evaluated. (Registration Number: ChiCTR-OIC-17013726). RESULTS: Forty patients enrolled, all of whom received 2 doses of sintilimab, and 37 underwent radical resection. Twenty-one (52.5%) patients experienced neoadjuvant treatment-related adverse events (TRAEs). Four (10.0%) patients experienced grade 3-4 neoadjuvant TRAEs, and one patient had grade 5 TRAE. Eight patients achieved radiological partial response, resulting in an ORR of 20.0%. Among 37 patients, 15 (40.5%) achieved MPR, including 6 (16.2%) with a pathologic complete response in primary tumor and 3 (8.1%) in lymph nodes as well. Squamouse cell NSCLC exhibited superior response compared to adenocarcinoma (MPR: 48.4% VS. 0%). Decrease of maximum standardized uptake values (SUVmax) after sintilimab treatment correlated with pathological remission (p<0.00001). Baseline PD-L1 expression of stromal cells instead of tumor cells was correlated with pathological regression (p=0.0471). CONCLUSION: Neoadjuvant sintilimab was tolerable for NSCLC patients and 40.5% MPR rate is encouraging. The decrease of SUVmax after sintilimab might predict pathologic response.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32043180

RESUMO

PURPOSE: Investigate whether 18F-FDG PET-CT has the potential to predict the major pathologic response (MPR) to neoadjuvant sintilimab in resectable NSCLC patients, and the potential of sifting patients who probably benefit from immunotherapy. METHODS: Treatment-naive patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1 and 22). Surgery was performed between day 29 and 43. PET-CT was obtained at baseline and prior to surgery. The following lean body mass-corrected metabolic parameters were calculated by PET VCAR: SULmax, SULpeak, MTV, TLG, ΔSULmax%, ΔSULpeak%, ΔMTV%, ΔTLG%. PET responses were classified using PERCIST. The above metabolic information on FDG-PET was correlated with the surgical pathology. (Registration Number: ChiCTR-OIC-17013726). RESULTS: Thirty-six patients received 2 doses of sintilimab, all of whom underwent PET-CT twice and had radical resection (35) or biopsy (1). MPR occurred in 13 of 36 resected tumors (36.1%, 13/36). The degree of pathological regression was positively correlated with SULmax (p = 0.036) of scan-1, and was negatively correlated with all metabolic parameters of scan-2, and the percentage changes of the metabolic parameters after neoadjuvant therapy (p < 0.05). According to PERCIST, 13 patients (36.1%, 13/36) showed partial metabolic response (PMR), 21 (58.3%, 21/36) had stable metabolic disease, and 2 (5.6%, 2/36) had progressive metabolic disease (PMD). There was a significant correlation between the pathological response and the PET responses which were classified using PERCIST. All (100.0%) the PMR (ΔSULpeak% < - 30.0%) tumors showed MPR. CONCLUSIONS: 18F-FDG PET-CT can predict MPR to neoadjuvant sintilimab in resectable non-small cell lung cancer.

4.
Thorac Cancer ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020764

RESUMO

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive disease involving immunodeficiency for which chemotherapy is the standard treatment. Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) is widely used for primary or secondary prophylaxis of febrile neutropenia (FN) in chemotherapy. However, whether PEG-rhG-CSF influences immune cells, such as lymphocytes, remains unclear. METHODS: A total of 17 treatment-naïve SCLC patients were prospectively enrolled and divided into the PEG-rhG-CSF and control groups according to their FN risk. Longitudinal sampling of peripheral blood was performed before, after and 4-6 days after the first cycle of chemotherapy. Flow cytometry was used to assess lymphocyte subsets, including CD3+ T, CD4+ T, CD8+ T, NK, and B cells. The diversity and clonality of the T-cell receptor (TCR) repertoire was analyzed by next-generation sequencing. RESULTS: In the PEG-rhG-CSF group, the proportions of CD3+ T and CD4+ T cells had increased significantly (P = 0.002, P = 0.020, respectively), whereas there was no increase in CD8+ T cells. Further, TCR diversity increased (P = 0.009) and clonality decreased (P = 0.004) significantly after PEG-rhG-CSF treatment. However, these factors showed opposite trends before and after chemotherapy. Vß and Jß gene fragment types, which determine TCR diversity, were significantly amplified in the PEG-rhG-CSF group. The change in TCR diversity was significantly correlated with changes in the CD3+ T or CD4+ T cell proportions, but not the CD8+ T cell proportion. CONCLUSIONS: PEG-rhG-CSF regulates the immune status of SCLC patients; CD4+ T cells may be the main effector cells involved in this process. These findings may optimize the treatment of SCLC. KEY POINTS: PEG-rhG-CSF regulates SCLC immunity. PEG-rhG-CSF increased CD3+ T and CD4+ T cell proportions. PEG-rhG-CSF increased TCR diversity and decreased clonality in peripheral blood. Change in TCR diversity were correlated with CD3+ T or CD4+ T changes.

5.
Rev Esp Enferm Dig ; 1122020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32022568

RESUMO

Endoscopic procedures for the main pancreatic duct (MPD) are usually performed via major papilla. Minor papilla may be a feasible approach in some cases which attempts of cannulation through major papilla was also failed. Herein, we report the case of a novel method for the minor papilla cannulation.

6.
J Mater Chem B ; 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31993604

RESUMO

The synthesis of superparamagnetic nanoclusters is critical for ultra-sensitive magnetic resonance imaging (MRI). Herein, we describe the synthesis of water-soluble, biocompatible and superparamagnetic gadolinium-doped iron oxide nanoclusters (GdIO NCs) via a one-pot reaction by thermal decomposition of ferric oleate and gadolinium oleate precursors with α,ω-dicarboxyl poly(ethylene glycol) as a surfactant. The resulting water-dispersible GdIO NCs possess good stability and monodispersity with narrow size distribution, and exhibit superparamagnetic behaviors. We also explored the effect of gadolinium doping amounts on the magnetic properties and longitudinal (r1) and transverse relaxivity (r2) of the nanoclusters. In addition, the GdIO NCs can be functionalized with fluorescein isothiocyanate (FITC) while maintaining their magnetic properties and biocompatibility. The GdIO NCs and FITC conjugated NCs were preliminarily evaluated as MRI and fluorescent probes. The results show that the GdIO NCs provide an important nano-platform for theranostics with non-invasive MRI and optical monitoring capabilities.

7.
J Phys Chem Lett ; 11(3): 927-934, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31957447

RESUMO

High power conversion efficiency can be realized by using a ternary bulk heterojunction with complementary absorption spectra in organic solar cells. However, as the development of nonfullerene acceptors with a broad absorption spectrum makes the absorption efficiency of the photovoltaic devices close to optimal, such a strategy needs modifying. In particular, charge transfer between the two acceptors is necessary to be considered. Herein, we purposely design a ternary system based on PTB7-Th:COi8DFIC:ITIC-4F. Though the presence of ITIC-4F in PTB7-Th:COi8DFIC could not broaden the absorption spectrum obviously, the formed cascade-energy-level alignment is beneficial for promoting and balancing exciton separation and charge transport between the donor and two acceptors and even between the acceptors. Insights into the charge transport route in the completed system are provided via using the techniques including photoluminescence spectroscopy and pump-probe photoconductivity spectroscopy. This work provides a new idea for designing highly efficient ternary organic solar cells.

8.
Sci Total Environ ; 709: 135888, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31927426

RESUMO

As global climate warms, the occurrence frequency and loss of natural disaster are both increasing, posing a great threat to the sustainable development of human society. One of the most important approaches of disaster management is to prevent disaster and reduce disaster loss through fiscal expenditure of government; however, the optimal proportion of expenditure for disaster prevention and mitigation has always been a difficult issue that people concern about. First, this paper, after considering the impact of disaster on human capital, established a resident-manufacturer-government decision making model which contains the probability of disaster, and then solved the optimal proportion of government expenditure for disaster prevention and reduction as well as the expected economic growth rates under different conditions. Second, through numerical simulation method, this paper studied the impacts of such factors as coefficient of risk aversion and elasticity coefficient of substitution on the optimal proportion of disaster prevention and reduction expenditure. Third, through constant elasticity of substitution (CES) production function and ridge regression method, this paper verified the applicability of the proposed model with the data of the expenditures for disaster prevention and mitigation of Hunan Province in 2014. Finally, this paper summarized the research results and put forward corresponding suggestions on policy. The theoretical model proposed in this paper enriches the related researches of disaster economics, and the conclusions of empirical analysis can provide government departments with useful reference for the practice of disaster prevention and mitigation.

9.
Cancer Immunol Res ; 8(1): 146-154, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31719056

RESUMO

T-cell receptor (TCR)-based biomarkers might predict patient response to immune checkpoint blockade (ICB) but need further exploration and validation for that use. We sequenced complementarity-determining region 3 of TCRß chains isolated from PD-1+ CD8+ T cells to investigate its value for predicting the response to anti-programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1) therapy in patients with non-small cell lung cancer (NSCLC). Two independent patient cohorts (cohort A, n = 25; cohort B, n = 15) were used as discovery and validation sets, respectively. Pre- and post-ICB peripheral blood samples were collected. In cohort A, patients with high PD-1+ CD8+ TCR diversity before ICB treatment showed better response to ICB and progression-free survival (PFS) compared with patients with low diversity [6.4 months vs. 2.5 months, HR, 0.39; 95% confidence interval (CI), 0.17-0.94; P = 0.021]. The results were validated in cohort B. Pre-ICB PD-1+ CD8+ TCR diversity achieved an optimal Youden's index of 0.81 (sensitivity = 0.87 and specificity = 0.94) for differentiating the ICB response in the merged dataset (cohort A plus cohort B). Patients with increased PD-1+ CD8+ TCR clonality after ICB treatment had longer PFS (7.3 months vs. 2.6 months, HR, 0.26; 95% CI, 0.08-0.86; P = 0.002) than those with decreased clonality. Thus, TCR diversity and clonality in peripheral blood PD-1+ CD8+ T cells may serve as noninvasive predictors of patient response to ICB and survival outcomes in NSCLC.

10.
IEEE Trans Biomed Eng ; 67(1): 291-297, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31021758

RESUMO

OBJECTIVE: Although low-intensity transcranial ultrasound stimulation (TUS) enhances/suppresses neural oscillations and causes electroencephalography changes in the motor cortex, researchers have not clearly determined the manner in which the relative power and entropy of neural oscillations in the motor cortex vary with ultrasonic parameters, such as ultrasound intensity, stimulation duration (SD), and duty cycle. METHODS: In this paper, we use the transcranial ultrasound of different parameters to stimulate the mouse motor cortex, cause tail muscle contraction and movement, and simultaneously record local field potentials (LFPs) in the mouse motor cortex. The relative power and entropy of the LFPs under different ultrasonic parameters are analyzed. RESULTS: The relative power of the theta [4-8 Hz] frequency bands decreases with an increase in spatial-peak and pulse-average intensity (Isppa) at 0-0.5 s and 0.5-1 s; the relative power of the gamma [30-45 Hz] frequency bands increases with an increase in Isppa at 0-0.5 s and 0.5-1 s; the relative power each of the gamma [30-45 Hz] and high gamma [55-100 Hz] frequency bands increases with an increase in the SD at 0-0.5 s and 0.5-1 s; the entropy values decrease with increases in Isppa and SD at 0-0.5 s. CONCLUSION: The relative power and entropy of neural oscillations in the motor cortex can be modulated by TUS with different parameters, namely, ultrasound intensity and stimulation duration.

11.
Drug Deliv Transl Res ; 10(1): 23-33, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31240626

RESUMO

We have used a novel active hydraulic ventricular support drug delivery system (ASD) device, which is a non-transplant surgical approach, can adhere to heart surface, and deliver the drug directly into the epicardium. This study is intended to compare the effect of administration of nitroglycerine (NTG) through ASD and intravenous injection on the ischemic injury during acute myocardial infarction (AMI). 30 male SD rats were allocated into five groups (n = 6): sham, AMI, I.V., ASD high dose (ASDH), and ASD low dose (ASDL) respectively. Ligation of the left anterior descending (LAD) coronary artery was performed to induce myocardial infarction. Electrocardiograms were monitored, and serum myoglobin (Mb) was assessed. Hemodynamics was observed on pre- and post-operation. Hematoxylin and eosin (H&E) staining was performed for histological diagnosis. In all model animals, ligation of LAD provoked ST segment elevation and Mb level augmentation. In ASDH group, Mb showed obvious decrease as compared with other treatment groups. Hemodynamic parameters showed significant improvement in ASDH and ASDL groups than the I.V. group. H&E staining showed that AMI group rats had wavy fibers and loss of transverse striations while ASD group rats had obvious improvement. Unlike the I.V. group, ASD group rats showed significant vasodilation. Therefore, delivery of NTG through ASD to the cardiomyocytes could improve the therapeutic efficacy. A novel effective route for local delivery of agents to manage AMI has been proved.

12.
Eye (Lond) ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784704

RESUMO

PURPOSE: To compare the efficacy and safety of subthreshold micropulse laser (SML) with threshold conventional laser (TCL) in central serous chorioretinopathy (CSC). METHODS: Prospective, randomized, double-masked, non-inferiority, 12-week clinical trial. Patients were randomly assigned 1:1 to SML group or TCL group. Patients in the SML group were treated with 577 nm micropulse laser. The spot size was 160 µm, the duty cycle was 5% and exposure time was 0.2 s. The power was 50% threshold tested. Patients in the TCL group were treated with 577 nm continuous laser. The power was 100% threshold tested. The primary outcome was the mean change in best-corrected visual acuity (BCVA) at week 12, with a non-inferiority limit of five letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts. RESULTS: Eighty-eight patients were enroled. Seventy-seven patients were male. Forty-four patients were in SML group and 44 in TCL group. At week 12, SML was equivalent to TCL with a gain of 6.23 ± 8.59 and 6.61 ± 6.35 letters, respectively, (SML-TCL difference: -0.38 letters; 95% confidence interval (CI):-3.58-2.81; Pnon-inferiority = 0.0026). There was no statistically significant difference between the two groups (t = 0.240, P = 0.811). At week 12, the proportion of patients whose SRF had been totally absorbed was 63.63 and 81.82% respectively for SML and TCL groups. There was no statistically significant difference between the two groups (χ2 = 3.67, P = 0.056). CONCLUSIONS: Both SML and TCL can improve visual acuity in CSC. SML was non-inferior to TCL in the improvement of BCVA.

13.
Chin J Cancer Res ; 31(5): 749-758, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31814679

RESUMO

Objective: To evaluate the efficacy and safety profile of first-line bevacizumab (Bev)-containing pemetrexed-platinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer (NS-NSCLC). Methods: A total of 415 eligible patients with NS-NSCLC who received first-line pemetrexed-platinum chemotherapy at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between February 2010 and September 2017 were reviewed retrospectively: 309 Bev(-) and 106 Bev(+) cases. Bev was administered at 7.5 mg/kg every 3 weeks in the Bev(+) group. To reduce the risk of a selection bias, a propensity score-matching (PSM) was conducted and 105 pairs of Bev(-) and Bev(+) cases were identified. Results: The median duration of follow-up was 15.8 months. The median progression-free survival (PFS) was prolonged significantly in the Bev(+) group than in the Bev(-) group in overall (9.8vs. 7.8 months, P=0.006) and PSM pairs (9.8 vs. 6.6 months, P<0.001). Moreover, patients receiving maintenance therapy with pemetrexed plus Bev had longer PFS than those interrupted after induction chemotherapy, or those receiving mono-maintenance with pemetrexed (12.3vs. 4.8 vs. 8.6 months; P<0.001). Multivariate analyses revealed Bev to be one of the favorable prognostic factors for PFS, along with the predictor of maintenance therapy. Conclusions: First-line induction and maintenance therapy with Bev (7.5 mg/kg every 3 weeks) combined with pemetrexed-platinum chemotherapy was efficacious and superior to non-Bev chemotherapy in Chinese patients with advanced NS-NSCLC.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31840345

RESUMO

Potassium-ion batteries are promising for low-cost and large-scale energy storage applications, but the major obstacle to their application is the lack of safe and effective electrolytes. A phosphate-based fire retardant such as triethyl phosphate is now shown to work as a single solvent with potassium bis(fluorosulfonyl)imide at 0.9 m, in contrast to previous Li and Na systems where phosphates cannot work at low concentrations. This electrolyte is optimized at 2 m, where it exhibits the advantages of low cost, low viscosity, and high conductivity, as well as the formation of a uniform and robust salt-derived solid-electrolyte interphase layer, leading to non-dendritic K-metal plating/stripping with Coulombic efficiency of 99.6 % and a highly reversible graphite anode.

15.
Mov Disord ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31829467

RESUMO

BACKGROUND: Low-intensity transcranial ultrasound stimulation is a new noninvasive brain modulation method with high spatial resolution and high penetration depth. However, until now, it was unclear whether transcranial ultrasound stimulation has a significant effect on PD. OBJECTIVES: In order to evaluate the effect of transcranial ultrasound stimulation on PD. METHODS: We used transcranial ultrasound stimulation to modulate parkinsonian-related activity in mice administered MPTP and recorded local field potentials in the motor cortex before and after ultrasound stimulation. We analyzed neuronal oscillatory activity known to be relevant to the pathophysiology of PD. RESULTS: After ultrasound stimulation, mean power intensity in the beta band (13-30 Hz) significantly decreased, and the phase-amplitude coupling strength between the beta and high gamma (55-100 Hz) bands and between the beta and ripple (100-200 Hz) bands also became significantly weaker. CONCLUSIONS: This study demonstrates that ultrasonic neuromodulation can significantly decrease parkinsonian-related activity in mice administered MPTP. © 2019 International Parkinson and Movement Disorder Society.

16.
BMJ Open ; 9(12): e029589, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796475

RESUMO

OBJECTIVE: Clinical guidelines are designed to optimise patient care and provide efficient approaches for therapy. Epilepsy is a chronic brain disorder that continues to experience a considerable treatment gap due to non-standard recommendations. We assessed the reporting quality of clinical practice guidelines on epilepsy over the past 5 years to generate a reporting specification for this study. SETTING: Seven databases were searched in May 2018 focusing on the period from 2013 to 2018. These included Medline, EMBASE, PubMed, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, Wanfang and Chinese Science and Technology Journal Database (VIP). Reporting quality of epilepsy guidelines was assessed by two independent authors using the Reporting Items for practice Guidelines in HealThcare (RIGHT) approach. Spearman's correlation was used to assess inter-rater reliability. PARTICIPANTS: Participants with epilepsy or seizure, not limited by age, gender, course of disease or cause of epilepsy, were included. INTERVENTIONS: There were no limitations with regard to intervention. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome was the ability of the RIGHT tool to measure reporting quality. RESULTS: Twelve relevant guidelines were included in this study. The reporting quality was not high in any of the included guidelines. The highest reporting quality included a 'yes' proportion of 77.1%, whereas the worst included a corresponding proportion of 37.1%. Overall evaluation results showed that 16.7% of the included guidelines were of high quality, 75% were of medium quality and 8.3% were of low quality. The correlation between the two estimators was credible (ρ>0.7). CONCLUSIONS: Appraisal of these guidelines using the RIGHT tool revealed that the quality of reporting varied among guidelines. Items that exhibited low quality in most included guidelines were healthcare questions, rationale/explanation for recommendations, quality assurance, funding source(s) and role(s) of the funder, and limitations of the guideline. Thus, these aspects should receive greater attention in future guideline reporting.

17.
JAMA Oncol ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31876895

RESUMO

Importance: Immune checkpoint inhibitors of programmed cell death 1 (PD-1) and its ligand (PD-L1) have led to a paradigm shift in cancer treatment. Understanding the clinical efficacy and safety profile of these drugs is necessary for treatment strategy in clinical practice. Objective: To assess the differences between anti-PD-1 and anti-PD-L1 regarding efficacy and safety shown in randomized clinical trials across various tumor types. Data Sources: Systematic searches of PubMed, Cochrane CENTRAL, and Embase were conducted from January 1, 2000, to March 1, 2019. In addition, abstracts and presentations from all major conference proceedings were reviewed. Study Selection: All randomized clinical trials that compared anti-PD-1 and anti-PD-L1 with standard treatment in patients with cancer were selected as candidates. Retrospective studies, single-arm phase 1/2 studies, and trials comparing anti-PD-1 and anti-PD-L1 with other immunotherapies were excluded. Studies of anti-PD-1 and anti-PD-L1 therapy were screened and paired by the matching of clinical characteristics as mirror groups. Data Extraction and Synthesis: Three investigators independently extracted data from each study following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. Trial names, first author, year of publication, study design, National Clinical Trial identifier number, blinding status, study phase, pathologic characteristics, number of patients, patients' age and sex distribution, Eastern Cooperative Oncology Group Performance Status, lines of treatment, study drugs, biomarker status, follow-up time, incidence of adverse events, and hazard ratios (HRs) with 95% CIs for overall survival and progression-free survival were extracted. A random-effects model was applied for data analysis. Main Outcomes and Measures: Differences in OS between anti-PD-1 and anti-PD-L1 across different cancer types were assessed. An effect size was derived from each mirror group and then pooled across all groups using a random-effects model. Results: Nineteen randomized clinical trials involving 11 379 patients were included in the meta-analysis. Overall, anti-PD-1 exhibited superior overall survival (HR, 0.75; 95% CI, 0.65-0.86; P < .001) and progression-free survival (HR, 0.73; 95% CI, 0.56-0.96; P = .02) compared with anti-PD-L1. No significant difference was observed in their safety profiles. Sensitivity analysis presented consistency in the overall estimates across these analyses. Consistent results were observed through frequentist and bayesian approaches with the same studies. Conclusions and Relevance: Comprehensive analysis suggests that anti-PD-1 exhibited favorable survival outcomes and a safety profile comparable to that of anti-PD-L1, which may provide a useful guide for clinicians.

18.
J Thorac Oncol ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31843683

RESUMO

INTRODUCTION: Blood-based tumor mutational burden (bTMB) has been studied to differentiate non-small cell lung cancer (NSCLC) patients who would benefit from anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. METHODS: Three independent cohorts of NSCLC patients treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N=211 and OAK, N=462) and further validated in the third National Cancer Center cohort (NCC, N=64). RESULTS: bTMB-H (bTMB≥cut-off point) was not associated with favorable OS following immunotherapy regardless of the cut-off points in either the POPLAR and OAK or the NCC cohorts (P>0.05) due to its correlation with the circulating tumor DNA (ctDNA) amount, which was associated with poor OS. In the POPLAR and OAK cohorts, upon allele frequency (AF) adjustment, a high allele frequency bTMB (HAF-bTMB, mutation counts with an AF>5%) was strongly correlated with the ctDNA amount (Pearson's r=0.65), while a low allele frequency bTMB (LAF-bTMB, mutation counts with an AF≤5%) was not (Pearson's r=0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [[HR], 0.70; 95% confidence interval [CI], 0.52-0.95; P=0.02), progression-free survival (PFS) (HR, 0.62; 95% CI, 0.47-0.80; P<0.001), and the objective response rate (ORR) (P<0.001) following immunotherapy but not chemotherapy, with a cut-off point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR, 0.20; 95% CI, 0.05-0.84; P=0.02), PFS (HR, 0.30; 95% CI, 0.13-0.70; P=0.003), and the ORR (P=0.001). CONCLUSIONS: We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and the ORR following anti-PD-1/PD-L1 therapies in NSCLC patients, which needs to be prospectively validated.

19.
Brief Bioinform ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729524

RESUMO

Molecular representations play critical roles in researching drug design and properties, and effective methods are beneficial to assisting in the calculation of molecules and solving related problem in drug discovery. In previous years, most of the traditional molecular representations are based on hand-crafted features and rely heavily on biological experimentations, which are often costly and time consuming. However, recent researches achieve promising results using machine learning on various domains. In this article, we present a novel method named Smi2Vec-BiGRU that is designed for learning atoms and solving the single- and multitask binary classification problems in the field of drug discovery, which are the basic and also key problems in this field. Specifically, our approach transforms the molecule data in the SMILES format into a set of sample vectors and then feeds them into the bidirectional gated recurrent unit neural networks for training, which learns low-dimensional vector representations for molecular drug. We conduct extensive experiments on several widely used benchmarks including Tox21, SIDER and ClinTox. The experimental results show that our approach can achieve state-of-the-art performance on these benchmarking datasets, demonstrating the feasibility and competitiveness of our proposed approach.

20.
Int J Mol Sci ; 20(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731727

RESUMO

Fms-like receptor tyrosine kinase 3 (FLT3) has been emerging as an attractive target for the treatment of acute myeloid leukemia (AML). By modifying the structure of FN-1501, a potent FLT3 inhibitor, 24 novel 1H-pyrazole-3-carboxamide derivatives were designed and synthesized. Compound 8t showed strong activity against FLT3 (IC50: 0.089 nM) and CDK2/4 (IC50: 0.719/0.770 nM), which is more efficient than FN-1501(FLT3, IC50: 2.33 nM; CDK2/4, IC50: 1.02/0.39 nM). Compound 8t also showed excellent inhibitory activity against a variety of FLT3 mutants (IC50 < 5 nM), and potent anti-proliferative effect within the nanomolar range on acute myeloid leukemia (MV4-11, IC50: 1.22 nM). In addition, compound 8t significantly inhibited the proliferation of most human cell lines of NCI60 (GI50 < 1 µM for most cell lines). Taken together, these results demonstrated the potential of 8t as a novel compound for further development into a kinase inhibitor applied in cancer therapeutics.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA