Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 127
Filtrar
1.
Acta Pharm Sin B ; 14(9): 4102-4117, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39309485

RESUMEN

Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.

2.
Chin Med J (Engl) ; 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39307928

RESUMEN

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy (RT) following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed. Inverse probability of treatment weighting (IPTW) analysis was performed to address potential confounding factors. The primary focus of our evaluation was to assess the impact of RT on progression-free survival (PFS) and overall survival (OS). RESULTS: After IPTW analysis, 49 patients received durvalumab plus platinum-etoposide(EP) chemotherapy followed by RT (Durva + EP + RT) and 72 patients received immunochemotherapy (Durva + EP). The median OS was 17.2 months vs. 12.3 months (hazard ratio [HR]: 0.38, 95% CI: 0.17-0.85, P = 0.020), and the median PFS was 8.9 months vs. 5.9 months (HR: 0.56, 95% CI: 0.32-0.97, P = 0.030) in Durva + EP + RT and Durva + EP groups, respectively. Thoracic radiation therapy (TRT) resulted in longer OS (17.2 months vs. 14.7 months) and PFS (9.1 months vs. 7.2 months) compared to RT directed to other metastatic sites. Among patients with oligo-metastasis, RT also showed significant benefits, with a median OS of 17.4 months vs. 13.7 months and median PFS of 9.8 months vs. 5.9 months compared to no RT. Continuous durvalumab treatment beyond progression (TBP) prolonged OS compared to patients without TBP, in both the Durva + EP + RT (NA vs. 15.8 months, HR: 0.48, 95% CI: 0.14-1.63, P = 0.238) and Durva + EP groups (12.3 months vs. 4.3 months, HR: 0.29, 95% CI: 0.10-0.81, P = 0.018). Grade 3 or 4 adverse events occurred in 13 (26.5%) and 13 (18.1%) patients, respectively, in the two groups; pneumonitis was mostly low-grade. CONCLUSION: Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.

3.
Artículo en Inglés | MEDLINE | ID: mdl-39158352

RESUMEN

Lipid disorders are related to the risk of nonalcoholic fatty liver disease (NAFLD). Remnant cholesterol (RC), a nonclassical and once-neglected risk factor for NAFLD, has recently received new attention. In this study, we assessed the relationship between the RC levels and NAFLD risk. We searched across PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure, with no restrictions on publication languages. Retrospective cohort studies and cross-sectional studies were enrolled from the inception of the databases until August 6, 2023. A random-effect model was applied to construct the mean difference, and a 95% confidence interval was applied to assess the relationship between the RC levels and NAFLD risk. We used two methods to estimate RC levels: Calculated-1 subtracts low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol from total cholesterol; Calculated-2 uses the Friedewald formula for LDL-C when triglycerides are <4.0 mmol/L, otherwise directly measured. A total of 265 published studies were selected through preliminary retrieval. Of these, six studies met the inclusion requirements and were enrolled in the meta-analysis. The RC level in the NAFLD group was significantly higher than that in the non-NAFLD group (mean difference: 0.18, 95% confidence interval: 0.10-0.26, P < 0.00001). We conducted subgroup analyses of computational methods and geographic regions. Notably, in the subgroup analysis of Calculation Method 2, the NAFLD group had significantly higher RC levels than the non-NAFLD group. On the other hand, in Calculation Method 1, the difference between the two groups was insignificant. In both the Asian and non-Asian populations, the RC levels were significantly higher in the NAFLD group than in the non-NAFLD group. The association of RC with an increased NAFLD risk was not dependent on the triglyceride. This meta-analysis suggests that elevated RC levels are associated with an increased risk of NAFLD. In addition to the conventional risk factors for fatty liver, clinicians should be concerned about the RC levels in the clinic.

4.
Cancer Immunol Immunother ; 73(10): 201, 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39105880

RESUMEN

PURPOSE: To assess the efficacy and safety of concurrent hypofractionated radiotherapy plus anti-PD-1 antibody and SOX chemotherapy in the treatment of metastatic pancreatic cancer (mPC) after failure of first-line chemotherapy. METHODS: Patients with pathologically confirmed mPC who failed standard first-line chemotherapy were enrolled. The patients were treated with a regimen of hypofractionated radiotherapy, SOX chemotherapy, and immune checkpoint inhibitors at our institution. We collected the patients' clinical information and outcome measurements. The median progression-free survival (mPFS) was the primary endpoint of the study, followed by disease control rate (DCR), objective response rate (ORR), median overall survival (mOS) and safety. Exploratory analyses included biomarkers related to the benefits. RESULTS: Between February 24, 2021, and August 30, 2023, twenty-five patients were enrolled in the study, and twenty-three patients who received at least one dose of the study agent had objective efficacy evaluation. The mPFS was 5.48 months, the mOS was 6.57 months, and the DCR and ORR were 69.5% and 30.4%, respectively. Among the seven patients who achieved a PR, the median duration of the response was 7.41 months. On-treatment decreased serum CA19-9 levels were associated with better overall survival. Besides, pretreatment inflammatory markers were associated with tumor response and survival. CONCLUSIONS: Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with these combination therapies in patients with refractory mPC. On-treatment decreased serum CA19-9 levels and pretreatment inflammatory markers platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH) might be biomarkers related to clinical benefits. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/showproj.html?proj=130211 , identifier: ChiCTR2100049799, date of registration: 2021-08-09.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Hipofraccionamiento de la Dosis de Radiación , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/terapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ácido Oxónico/uso terapéutico , Ácido Oxónico/administración & dosificación , Quimioradioterapia/métodos , Tegafur/uso terapéutico , Tegafur/administración & dosificación , Gemcitabina , Metástasis de la Neoplasia
5.
iScience ; 27(6): 109966, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38832014

RESUMEN

Ambitious action plans have been launched to address climate change and air pollution. Through coupling the IMED|CGE, GAINS, and IMED|HEL models, this study investigate the impacts of implementing carbon neutrality and clean air policies on the energy-environment-health-economy chain in the Beijing-Tianjin-Hebei-Henan-Shandong-Shanxi region of China. Results show that Shandong holds the largest reduction in energy consumption and carbon emissions toward the 1.5°C target. Shandong, Henan, and Hebei are of particularly prominent pollutant reduction potential. Synergistic effects of carbon reduction on decreasing PM2.5 concentration will increase in the future, specifically in energy-intensive regions. Co-deployment of carbon reduction and end-of-pipe technologies are beneficial to decrease PM2.5-related mortalities and economic loss by 4.7-12.9% in 2050. Provincial carbon reduction cost will be higher than monetary health benefits after 2030, indicating that more zero-carbon technologies should be developed. Our findings provide scientific enlightenment on policymaking toward achieving carbon reduction and pollution mitigation from multiple perspectives.

6.
Signal Transduct Target Ther ; 9(1): 143, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38844468

RESUMEN

Metastatic pancreatic cancer (mPC) has a dismal prognosis. Herein, we conducted a prospective, multicentre, single-arm, phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine (PAAG) in patients with first-line mPC (NCT05493995). The primary endpoints included the objective response rate (ORR) and disease control rate (DCR), while secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), and safety. In 66 patients analysed for efficacy, the best response, indicated by the ORR, was recorded at 50.0% (33/66) (95% CI, 37.4-62.6%), with 33 patients achieving partial response (PR). Notably, the DCR was 95.5% (63/66, 95% CI, 87.3-99.1%). The median PFS (mPFS) and OS (mOS) were 8.8 (95% CI, 8.1-11.6), and 13.7 (95% CI, 12.4 to not reached) months, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 39.4% of patients (26/66). In prespecified exploratory analysis, patients with altered SWI/SNF complex had a poorer PFS. Additionally, low serum CA724 level, high T-cell recruitment, low Th17 cell recruitment, and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy. In conclusion, PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC. The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.


Asunto(s)
Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Gemcitabina , Indoles , Paclitaxel , Neoplasias Pancreáticas , Quinolinas , Humanos , Masculino , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Femenino , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacología , Persona de Mediana Edad , Anciano , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Indoles/administración & dosificación , Indoles/uso terapéutico , Albúminas/administración & dosificación , Albúminas/efectos adversos , Quinolinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios Prospectivos , Adulto , Metástasis de la Neoplasia , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología
7.
Mol Ther Nucleic Acids ; 35(2): 102215, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38784179

RESUMEN

[This retracts the article DOI: 10.1016/j.omtn.2019.10.047.].

8.
Lung Cancer ; 192: 107827, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38795459

RESUMEN

BACKGROUND: Non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements is a molecular subset that exhibits favorable responses to tyrosine kinase inhibitor (TKI) treatment than chemotherapy. This study investigated real-world treatment patterns and survival outcomes among patients with ROS1-rearranged advanced NSCLC. METHODS: We conducted a retrospective analysis of patients with ROS1-rearranged advanced NSCLC treated in four different hospitals in China from August 2018 to March 2022. The study analyzed gene fusion distribution, resistance patterns, and survival outcomes. RESULTS: ROS1 rearrangement occurs in 1.8 % (550/31,225) of our study cohort. CD74 was the most common ROS1 fusion partner, accounting for 45.8 %. Crizotinib was used in 73.9 % of patients in the first-line treatment, and an increased use of chemotherapy, ceritinib, and lorlatinib was seen in the second-line setting. Lung (43.2 %) and brain (27.6 %) were the most common sites of progression in first-line setting, while brain progression (39.2 %) was the most common site of progression in second-line. Median overall survival was 46 months (95 % confidence intervals: 39.6-52.4). First-line crizotinib use yielded significantly superior survival outcomes over chemotherapy in terms of progression-free (18.5 vs. 6.0; p < 0.001) and overall survival (49.8 vs. 37; p = 0.024). The choice of treatment in the latter line also had survival implications, wherein survival outcomes were better when first-line crizotinib was followed by sequential TKI therapy than first-line chemotherapy followed by TKI therapy. CONCLUSIONS: Our study provided insights into the real-world treatment, drug resistance patterns, and survival outcomes among patients with ROS1-rearranged NSCLC. This information serves as a valuable reference for guiding the treatment of this molecular subset of NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Crizotinib , Reordenamiento Génico , Neoplasias Pulmonares , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Masculino , Proteínas Proto-Oncogénicas/genética , Femenino , Proteínas Tirosina Quinasas/genética , Persona de Mediana Edad , Anciano , Crizotinib/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Tasa de Supervivencia , Pronóstico , Resistencia a Antineoplásicos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Pirazoles/uso terapéutico , China/epidemiología , Aminopiridinas , Antígenos de Diferenciación de Linfocitos B , Antígenos de Histocompatibilidad Clase II , Lactamas
9.
J Exp Clin Cancer Res ; 43(1): 128, 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38685050

RESUMEN

BACKGROUND: Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Radiotherapy could activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance. METHODS: We used databases to detect the expression of MIF in NSCLC and its relationship with prognosis. We analyzed the effects of targeted blockade of the MIF/CD74 axis on the polarization and function of microglia during radiotherapy using flow cytometry. The mouse model of brain metastasis was used to assess the effect of targeted blockade of MIF/CD74 axis on the growth of brain metastasis. RESULT: Our findings reveals that the macrophage migration inhibitory factor (MIF) was highly expressed in NSCLC and is associated with the prognosis of NSCLC. Mechanistically, we demonstrated CD74 inhibition reversed radiation-induced AKT phosphorylation in microglia and promoted the M1 polarization in combination of radiation. Additionally, blocking the MIF-CD74 interaction between NSCLC and microglia promoted microglia M1 polarization. Furthermore, radiation improved tumor hypoxia to decrease HIF-1α dependent MIF secretion by NSCLC. MIF inhibition enhanced radiosensitivity for brain metastasis via synergistically promoting microglia M1 polarization in vivo. CONCLUSIONS: Our study revealed that targeting the MIF-CD74 axis promoted microglia M1 polarization and synergized with radiotherapy for brain metastasis in NSCLC.


Asunto(s)
Antígenos de Diferenciación de Linfocitos B , Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Antígenos de Histocompatibilidad Clase II , Neoplasias Pulmonares , Factores Inhibidores de la Migración de Macrófagos , Microglía , Animales , Femenino , Humanos , Ratones , Antígenos de Diferenciación de Linfocitos B/metabolismo , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Antígenos de Histocompatibilidad Clase II/metabolismo , Oxidorreductasas Intramoleculares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Microglía/metabolismo , Microglía/patología
10.
Cancer Immunol Immunother ; 73(4): 74, 2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38451314

RESUMEN

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Inestabilidad de Microsatélites , Neoplasias , Humanos , Estudios Retrospectivos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , China , Respuesta Patológica Completa
11.
Acta Pharm Sin B ; 14(2): 765-780, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38322349

RESUMEN

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8+ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated ß-cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile ß-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

12.
Front Immunol ; 15: 1210859, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38361920

RESUMEN

Background: Pancreatic adenocarcinoma carries a grim prognosis, and there are few recognized effective second-line treatment strategies. We attempted to evaluate the efficacy and safety of a combination of S-1, sintilimab, and anlotinib as a second-line treatment in pancreatic cancer patients with liver metastasis. Methods: Pancreatic cancer patients with liver metastases were recruited. S-1 was administered orally at 25 mg/m2 bid, anlotinib was administered orally at 12 mg qd from day 1 to day 14, and sintilimab was administered intravenously at 200 mg on day 1. This method was repeated every 21 days, and the therapeutic effect was evaluated every 3 cycles. The primary outcome was the objective response rate (ORR). Results: Overall, 23 patients were enrolled in this study of whom 19 patients had objective efficacy evaluation. The ORR was 10.5% (95% CI 0.4%-25.7%) in the evaluable population. The progression-free survival (PFS) was 3.53 (95% CI 2.50-7.50) months, and the overall survival (mOS) was 8.53 (95% CI 4.97-14.20) months. Grade 3 adverse events were 26.1%, and no grade 4 or above adverse events occurred. High-throughput sequencing was performed on the tumor tissues of 16 patients; patients with HRD-H (n = 10) had shorter PFS than those with HRD-L (n = 6) (2.43 vs. 5.45 months; P = 0.043), but there was no significant difference in OS between the two groups (4.43 vs. 9.35 months; P = 0.11). Conclusions: This study suggests the advantage of S-1 combined with sintilimab and anlotinib in extending OS as a second-line therapy in pancreatic cancer patients with liver metastasis. Clinical Trial Registration: ChiCTR2000030659.


Asunto(s)
Adenocarcinoma , Anticuerpos Monoclonales Humanizados , Indoles , Neoplasias Hepáticas , Neoplasias Pancreáticas , Quinolinas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico
13.
ACS Nano ; 18(4): 3234-3250, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38214975

RESUMEN

A brain-targeting nanodelivery system has been a hot topic and has undergone rapid progression. However, due to various obstacles such as the intestinal epithelial barrier (IEB) and the blood-brain barrier (BBB), few nanocarriers can achieve brain-targeting through oral administration. Herein, an intelligent oral brain-targeting nanoparticle (FTY@Man NP) constructed from a PLGA-PEG skeleton loaded with fingolimod (FTY) and externally modified with mannose was designed in combination with a glucose control strategy for the multitarget treatment of Alzheimer's disease (AD). The hydrophilic and electronegative properties of the nanoparticle facilitated its facile penetration through the mucus barrier, while the mannose ligand conferred IEB targeting abilities to the nanoparticle. Subsequently, glycemic control allowed the mannose-integrated nanoparticle to hitchhike the glucose transporter 1 (GLUT1) circulation across the BBB. Finally, the released FTY modulated the polarity of microglia from pro-inflammatory M1 to anti-inflammatory M2 and normalized the activated astrocyte, enhancing the clearance of toxic protein Amyloid-ß (Aß) while alleviating oxidative stress and neuroinflammation. Notably, both in vitro and in vivo results have consistently demonstrated that the oral administration of FTY@Man NP could effectively traverse the multiple barriers, thereby exerting significant therapeutic effects. This breakthrough holds the promise of realizing a highly effective orally administered treatment for AD.


Asunto(s)
Enfermedad de Alzheimer , Nanopartículas , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Transportador de Glucosa de Tipo 1/metabolismo , Manosa , Barrera Hematoencefálica/metabolismo , Péptidos beta-Amiloides/metabolismo
14.
Artículo en Chino | WPRIM (Pacífico Occidental) | ID: wpr-1017979

RESUMEN

Objective:To investigate the efficacy and safety of intravenous thrombolysis and antiplatelet therapy in patients with stroke warning syndrome (SWS), as well as influencing factors of the outcome in patients with SWS.Method:Patients with SWS admitted to the 521 st Hospital of Ordnance Group from June 1, 2018 to December 31, 2023 were retrospectively included. Some patients were treated with ateplase intravenous thrombolysis, followed by oral antiplatelet therapy; some patients only received antiplatelet therapy. The main outcome measure was the modified Rankin Scale score at 90 days after onset, with a score of 0-2 defined as good outcome. Results:A total of 35 patients with SWS were included, including 26 males (74.3%) with an age of 58.29±11.06 years. Nineteen patients (54.3%) received intravenous thrombolysis, and 27 (77.1%) had good outcome at 90 days. There was no statistically significant difference in demographic, baseline data, and good outcome between the intravenous thrombolysis group and the antiplatelet therapy group. One patient had new stroke and one had transient ischemic attack in the intravenous thrombolysis group. There were statistically significant differences in ABCD2 score, systolic blood pressure, low-density lipoprotein cholesterol, fasting blood glucose, highest National Institutes of Health Stroke Scale (NIHSS) score at onset, and symptom duration between the good outcome group and the poor outcome group (all P<0.05). Conclusions:The efficacy of intravenous thrombolysis is similar to that of antiplatelet drugs alone in treating SWS. ABCD2 score, systolic blood pressure, low-density lipoprotein cholesterol, fasting blood glucose, highest NIHSS score at onset, and duration of symptoms may be influencing factors for the outcome of patients with SWS.

15.
Environ Sci Technol ; 58(1): 33-42, 2024 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-38109378

RESUMEN

Electrifying freight trucks will be key to alleviating air pollution burdens on disadvantaged communities and mitigating climate change. The United States plans to pursue this aim by adding vehicle charging infrastructure along specific freight corridors. This study explores the coevolution of the electricity grid and freight trucking landscape using an integrated assessment framework to identify when each interstate and drayage corridor becomes advantageous to electrify from a climate and human health standpoint. Nearly all corridors achieve greenhouse gas emission reductions if electrified now. Most can reduce health impacts from air pollution if electrified by 2040 although some corridors in the Midwest, South, and Mid-Atlantic regions remain unfavorable to electrify from a human health standpoint, absent policy support. Recent policy, namely, the Inflation Reduction Act, accelerates this timeline to 2030 for most corridors and results in net human health benefits on all corridors by 2050, suggesting that near-term investments in truck electrification, particularly drayage corridors, can meaningfully reduce climate and health burdens.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Gases de Efecto Invernadero , Estados Unidos , Humanos , Emisiones de Vehículos/análisis , Vehículos a Motor , Contaminación del Aire/análisis , Electricidad , Contaminantes Atmosféricos/análisis
16.
Curr Opin Biotechnol ; 85: 103045, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38096768

RESUMEN

With the booming development of nanotechnology, nanomedicines have made considerable progress in the pharmaceutical field. However, the number of nanodrugs approved for clinical treatment is very limited. The main obstacles stem from the complexity of nanomedicine composition, tumor heterogeneity, complexity and incomplete understanding of nanotumor interactions, uncontrollable scaling, high production costs, and uncertainty of regulations and standards. This review article described the current stage of nanomedicines and highlighted the challenges, strategies, and opportunities for clinical translation of nanomedicines.


Asunto(s)
Nanopartículas , Neoplasias , Humanos , Nanomedicina , Nanotecnología , Neoplasias/terapia , Sistemas de Liberación de Medicamentos
17.
Biochim Biophys Acta Mol Basis Dis ; 1870(3): 166994, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38141838

RESUMEN

Radiation injury of blood vessels (RIBV) is a serious long-term complication of radiotherapy, characterized by the development of atherosclerosis. The involvement of vascular smooth muscle cells (VSMCs) senescence in the pathogenesis of radiation-induced atherosclerosis has been implicated, yet the precise mechanisms governing VSMCs senescence remain inadequately comprehended. In this study, the senescence of VSMCs was examined by employing SA-ß-gal staining and assessing the expression of p16 and p21, both in vivo and in vitro. Our findings revealed that ionizing radiation (IR) has the potential to augment cellular senescence. In addition, IR significantly activated the NF-κB pathway, as evidenced by increased p65 nuclear translocation, phospho-p65 expression, and enhanced binding ability of p65 (EMSA). Furthermore, a decrease in HMGB2 expression following exposure to IR was observed via Western blot analysis, while CTCF expression remained unchanged. Interestingly, the formation of CTCF spatial clustering was detected under super-resolution fluorescence microscopy. Concurrently, the ChIP technique identified the facilitation of the interaction between CTCF and p16 gene through IR. The inhibition of CTCF or the overexpression of HMGB2 through lentiviruses effectively eliminates the formation of CTCF clusters and the upregulation of p16 and p21 after IR. Inhibition of NF-κB activation induced by IR by PDTC (100 µM) led to a decrease in the staining of SA-ß-gal, a reduction in p16 expression, an increase in HMGB2 protein expression and a decrease in CTCF clusters formation. This study provided significant insights into the role and mechanism of IR in VSMCs senescence by regulating NF-κB/CTCF/p16 pathway.


Asunto(s)
Aterosclerosis , FN-kappa B , Humanos , FN-kappa B/metabolismo , Músculo Liso Vascular/metabolismo , Proteína HMGB2/metabolismo , Proteína HMGB2/farmacología , Senescencia Celular , Radiación Ionizante , Aterosclerosis/metabolismo
18.
Comput Struct Biotechnol J ; 21: 5839-5850, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38074472

RESUMEN

Generative adversarial networks (GANs) have successfully generated functional protein sequences. However, traditional GANs often suffer from inherent randomness, resulting in a lower probability of obtaining desirable sequences. Due to the high cost of wet-lab experiments, the main goal of computer-aided antibody optimization is to identify high-quality candidate antibodies from a large range of possibilities, yet improving the ability of GANs to generate these desired antibodies is a challenge. In this study, we propose and evaluate a new GAN called the Language Model Guided Antibody Generative Adversarial Network (AbGAN-LMG). This GAN uses a language model as an input, harnessing such models' powerful representational capabilities to improve the GAN's generation of high-quality antibodies. We conducted a comprehensive evaluation of the antibody libraries and sequences generated by AbGAN-LMG for COVID-19 (SARS-CoV-2) and Middle East Respiratory Syndrome (MERS-CoV). Results indicate that AbGAN-LMG has learned the fundamental characteristics of antibodies and that it improved the diversity of the generated libraries. Additionally, when generating sequences using AZD-8895 as the target antibody for optimization, over 50% of the generated sequences exhibited better developability than AZD-8895 itself. Through molecular docking, we identified 70 antibodies that demonstrated higher affinity for the wild-type receptor-binding domain (RBD) of SARS-CoV-2 compared to AZD-8895. In conclusion, AbGAN-LMG demonstrates that language models used in conjunction with GANs can enable the generation of higher-quality libraries and candidate sequences, thereby improving the efficiency of antibody optimization. AbGAN-LMG is available at http://39.102.71.224:88/.

19.
BMC Bioinformatics ; 24(1): 486, 2023 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-38114906

RESUMEN

BACKGROUND: Automatic and accurate extraction of diverse biomedical relations from literature is a crucial component of bio-medical text mining. Currently, stacking various classification networks on pre-trained language models to perform fine-tuning is a common framework to end-to-end solve the biomedical relation extraction (BioRE) problem. However, the sequence-based pre-trained language models underutilize the graphical topology of language to some extent. In addition, sequence-oriented deep neural networks have limitations in processing graphical features. RESULTS: In this paper, we propose a novel method for sentence-level BioRE task, BioEGRE (BioELECTRA and Graph pointer neural net-work for Relation Extraction), aimed at leveraging the linguistic topological features. First, the biomedical literature is preprocessed to retain sentences involving pre-defined entity pairs. Secondly, SciSpaCy is employed to conduct dependency parsing; sentences are modeled as graphs based on the parsing results; BioELECTRA is utilized to generate token-level representations, which are modeled as attributes of nodes in the sentence graphs; a graph pointer neural network layer is employed to select the most relevant multi-hop neighbors to optimize representations; a fully-connected neural network layer is employed to generate the sentence-level representation. Finally, the Softmax function is employed to calculate the probabilities. Our proposed method is evaluated on three BioRE tasks: a multi-class (CHEMPROT) and two binary tasks (GAD and EU-ADR). The results show that our method achieves F1-scores of 79.97% (CHEMPROT), 83.31% (GAD), and 83.51% (EU-ADR), surpassing the performance of existing state-of-the-art models. CONCLUSION: The experimental results on 3 biomedical benchmark datasets demonstrate the effectiveness and generalization of BioEGRE, which indicates that linguistic topology and a graph pointer neural network layer explicitly improve performance for BioRE tasks.


Asunto(s)
Lenguaje , Redes Neurales de la Computación , Minería de Datos , Lingüística , Procesamiento de Lenguaje Natural
20.
Exploration (Beijing) ; 3(4): 20210111, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37933241

RESUMEN

In the biomedical and pharmaceutical fields, cyclodextrin (CD) is undoubtedly one of the most frequently used macrocyclic compounds as the host molecule because it has good biocompatibility and can increase the solubility, bioavailability, and stability of hydrophobic drug guests. In this review, we generalized the unique properties of CDs, CD-related supramolecular nanocarriers, supramolecular controlled release systems, and targeting systems based on CDs, and introduced the paradigms of these nanomedicines. In addition, we also discussed the prospects and challenges of CD-based supramolecular nanomedicines to facilitate the development and clinical translation of these nanomedicines.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA