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1.
Chemistry ; : e202401350, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38700514

RESUMEN

An unprecedented 1,5-addition/N-1,4-addition cascade reaction is established via palladium hydride catalysis. A variety of polysubstituted dihydropyrrole skeletons are constructed in high yield and with exclusively >20:1 diastereoselectivity. An enantioselective protocol of this design is also developed to provide a novel access to enantioenriched dihydropyrroles.

2.
J Nucl Med ; 65(Suppl 1): 38S-45S, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38719241

RESUMEN

Radiopharmaceuticals play a critical role in nuclear medicine, providing novel tools for specifically delivering radioisotopes for the diagnosis and treatment of cancers. As the starting point for developing radiopharmaceuticals, cancer-specific biomarkers are important and receive worldwide attention. This field in China is currently experiencing a rapid expansion, with multiple radiotracers targeting novel targets being developed and translated into clinical studies. This review provides a brief overview of the exploration of novel imaging targets, preclinical evaluation of their targeting ligands, and translational research in China from 2020 to 2023, for detecting cancer, guiding targeted therapy, and visualizing the immune microenvironment. We believe that China will play an even more important role in the development of nuclear medicine in the world in the future.


Asunto(s)
Biomarcadores de Tumor , Neoplasias , Trazadores Radiactivos , Humanos , China , Biomarcadores de Tumor/metabolismo , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Radiofármacos , Animales
3.
Sensors (Basel) ; 24(5)2024 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-38475180

RESUMEN

In this study, an electric oil and gas actuator based on fractional-order PID position feedback control is proposed, through which the damping coefficient of the suspension system is adjusted to realize the active control of the suspension. An FOPID algorithm is used to control the motor's rotational angle to realize the damping adjustment of the suspension system. In this process, the road roughness is collected by the sensors as the criterion of damping adjustment, and the particle swarm algorithm is utilized to find the optimal objective function under different road surface slopes, to obtain the optimal cornering value. According to the mathematical and physical model of the suspension system, the simulation model and the corresponding test platform of this type of suspension system are built. The simulation and experimental results show that the simulation results of the fractional-order nonlinear suspension model are closer to the actual experimental values than those of the traditional linear suspension model, and the accuracy of each performance index is improved by more than 18.5%. The designed active suspension system optimizes the body acceleration, suspension dynamic deflection, and tire dynamic load to 89.8%, 56.7%, and 73.4% of the passive suspension, respectively. It is worth noting that, compared to traditional PID control circuits, the FOPID control circuit designed for motors has an improved control performance. This study provides an effective theoretical and empirical basis for the control and optimization of fractional-order nonlinear suspension systems.

4.
Front Pharmacol ; 15: 1285946, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38318142

RESUMEN

Objective: To compare the intervention effects and pharmacoeconomic advantages of Fufang Huangbai Fluid (FFHB) hydropathic compress versus Antimicrobial Calcium Alginate Wound Dressing (ACAWD) in the treatment of diabetic foot infections (DFI). Methods: Patients with DF who were hospitalized in the peripheral vascular Department of Dongzhimen Hospital of Beijing University of Chinese Medicine from December 2020 to February 2022 and met the inclusion and excluding criteria were allocated into the experimental group and control group through minimization randomization. The experimental group was treated with FFHB hydropathic compress for 2 weeks, while the control group was treated with ACAWD for the same duration. The wound healing of both groups was monitored for 1 month post-discharge. Clinical data from all eligible patients were collected, and differences in various indices between cohorts were analyzed. Results: 22 in the experimental group (including two fell off) and 20 in the control group. After the treatment, the negative rate of wound culture in the experimental group was 30% and that in the control group was 10%, There was no significant difference in the negative rate of wound culture and change trend of minimum inhibitory concentration (MIC) value of drug sensitivity (p > 0.05). The infection control rate of the experimental group was 60%, and that of the control group was 25%. The difference between the two groups was statistically significant (χ2 = 5.013, p = 0.025). The median wound healing rate of the experimental group was 34.4% and that of the control group was 33.3%. There was no significant difference between the two groups (p > 0.05). During the follow-up 1 month later, the wound healing rate in the experimental group was higher, and the difference was statistically significant (p = 0.047). Pharmacoeconomic evaluations indicated that the experimental group had greater cost-effectiveness compared to the control group. Conclusion: In the preliminary study, FFHB demonstrated comparable pathogenic and clinical efficacy to ACAWD in the treatment of mild DF infection, and exhibited superior pharmacoeconomic advantages. With the aid of infection control, the wound healing rate in the FFHB group showed notable improvement. Nevertheless, due to the limited sample size, larger-scale studies are warranted to further validate these findings. Clinical Trial Registration: (https://www.chictr.org.cn/showproj.aspx?proj=66175), identifier (ChiCTR2000041443).

5.
Int J Biol Macromol ; 257(Pt 1): 128569, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38065443

RESUMEN

This work aimed to investigate the combined effect of ultrasound (US) treatment and κ-carrageenan (KC) addition on the gelling properties and rheological behaviors of myofibrillar protein (MP). Without US treatment, the KC incorporation promoted the gel strength and water-holding capacity (WHC) of MP gels. These properties were further improved by 20 min US treatment with gel strength of 98.61 g and WHC of 79.87 %, which was mainly attributed to changes associated with hydrophobic interactions and disulfide bonds and the transformation from α-helix to ß-sheet in MP gels. In addition, US treatment for 20 min effectively resulted in a more homogeneous polymer distribution of the MP-KC mixed system, leading to lower particle size and the largest G' and G″ values of the MP-KC mixed gels. However, longer US treatment times (30, 40 and 50 min) rendered lower gel strength, WHC, storage modulus and loss modulus of MP-KC mixed gels, which was mainly due to the formation of loose and disordered gel structures. Our present results indicated that the application of US to MP for an intermediate treatment time (20 min) combined with KC provides a potential and novel strategy to promote the gel qualities of heat-induced MP gels.


Asunto(s)
Proteínas Musculares , Carragenina , Geles/química , Proteínas Musculares/química , Interacciones Hidrofóbicas e Hidrofílicas , Tamaño de la Partícula , Reología
6.
Nat Commun ; 14(1): 4493, 2023 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-37495604

RESUMEN

Atomic-scale precision alignment is a bottleneck in the fabrication of next-generation nanoelectronics. In this study, a redox-coupled inherently selective atomic layer deposition (ALD) is introduced to tackle this challenge. The 'reduction-adsorption-oxidation' ALD cycles are designed by adding an in-situ reduction step, effectively inhibiting nucleation on copper. As a result, tantalum oxide exhibits selective deposition on various oxides, with no observable growth on Cu. Furthermore, the self-aligned TaOx is successfully deposited on Cu/SiO2 nanopatterns, avoiding excessive mushroom growth at the edges or the emergence of undesired nucleation defects within the Cu region. The film thickness on SiO2 exceeds 5 nm with a selectivity of 100%, marking it as one of the highest reported to date. This method offers a streamlined and highly precise self-aligned manufacturing technique, which is advantageous for the future downscaling of integrated circuits.

7.
Bioorg Med Chem Lett ; 91: 129382, 2023 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-37348571

RESUMEN

Prostate-specific membrane antigen (PSMA) has been proved as a specific target for diagnosis and treatment of prostate cancer (PCa). Recently, oxalyldiaminopropionic acid (ODAP)-Urea-based ligands showed the potential as a new scaffold for developing radiotracers to image PCa. In this study, we synthesized seven ODAP-Urea-Lys derivatives characterized with p-bromobenzyl group conjugated to lysine. The ligands showed medium-to-high potency, with Ki values ranging from 27.9 nM to 0.94 nM. The ligands could be efficiently radiolabeled with 68Ga, in high purity. Radioligands were stable and showed PSMA specific cellular uptake, in PSMA++ LNCaP cells and PSMA+ 22Rv1 cells over PSMA- PC3 cells. MicroPET imaging was performed in 22Rv1 tumor-bearing mice and 68Ga-ligand-1 showed the best characteristics among the seven ligands, with the highest tumor uptake (SUVmax: 0.56 ± 0.07). A biodistribution study was also performed. ODAP-Urea-Lys-p-bromobenzyl could be used to image prostate cancer in vivo, and the ligands could have high binding potency. The future investigation is still necessary to improve the tumor-specific uptake of this class of ligands and reducing the non-specific uptake in normal organs.


Asunto(s)
Neoplasias de la Próstata , Urea , Masculino , Humanos , Animales , Ratones , Urea/química , Lisina/metabolismo , Radioisótopos de Galio , Tomografía de Emisión de Positrones/métodos , Ligandos , Distribución Tisular , Línea Celular Tumoral , Antígenos de Superficie/metabolismo , Glutamato Carboxipeptidasa II/metabolismo , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo
8.
Chemistry ; 29(44): e202301105, 2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37243903

RESUMEN

An expanding body of evidence suggests that specifically targeting hydrogen sulfide (H2 S) might potentially benefit both tumor diagnosis and treatment, but there is still a lack of cancer-targeted molecular tools for in vivo applications. Here, we report the first ligand-directed H2 S-specific near-infrared fluorescent sensor PSMA-Cy7-NBD and scavenger PSMA-Py-NBD that target the prostate-specific membrane antigen (PSMA). PSMA-Cy7-NBD displays a 53-fold off-on fluorescence response to H2 S at 803 nm with high specificity. PSMA-Py-NBD can scavenge H2 S fast (k2 =30.8 M-1 s-1 at 25 °C) without interference from biothiols. Both tools are highly water-soluble and can be transported selectively into PSMA-expressing prostate cancer cells. Endogenous H2 S levels in murine 22Rv1 tumor models can be imaged and downregulated by intravenous injection of PSMA-Cy7-NBD and PSMA-Py-NBD, respectively. These tools could potentially help to investigate H2 S cancer biology and with related therapies.


Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Animales , Ratones , Neoplasias de la Próstata/diagnóstico por imagen , Ligandos , Diagnóstico por Imagen , Línea Celular Tumoral
9.
Chem Sci ; 14(9): 2461-2466, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36873849

RESUMEN

A conceptually new methodology to give unusual cyclization products from usual migration substrates was disclosed. The highly complex and structurally important and valuable spirocyclic compounds were produced through radical addition, intramolecular cyclization and ring opening instead of usual migration to the di-functionalization products of olefins. Furthermore, a plausible mechanism was proposed based on a series of mechanistic studies including radical trapping, radical clock, verification experiments of intermediates, isotope labeling and KIE experiments.

10.
Nat Commun ; 14(1): 974, 2023 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-36810592

RESUMEN

Genetic encoding of noncanonical amino acid (ncAA) for site-specific protein modification has been widely applied for many biological and therapeutic applications. To efficiently prepare homogeneous protein multiconjugates, we design two encodable noncanonical amino acids (ncAAs), 4-(6-(3-azidopropyl)-s-tetrazin-3-yl) phenylalanine (pTAF) and 3-(6-(3-azidopropyl)-s-tetrazin-3-yl) phenylalanine (mTAF), containing mutually orthogonal and bioorthogonal azide and tetrazine reaction handles. Recombinant proteins and antibody fragments containing the TAFs can easily be functionalized in one-pot reactions with combinations of commercially available fluorophores, radioisotopes, PEGs, and drugs in a plug-and-play manner to afford protein dual conjugates to assess combinations of tumor diagnosis, image-guided surgery, and targeted therapy in mouse models. Furthermore, we demonstrate that simultaneously incorporating mTAF and a ketone-containing ncAA into one protein via two non-sense codons allows preparation of a site-specific protein triconjugate. Our results demonstrate that TAFs are doubly bio-orthogonal handles for efficient and scalable preparation of homogeneous protein multiconjugates.


Asunto(s)
Aminoácidos , Aminoacil-ARNt Sintetasas , Animales , Ratones , Aminoácidos/metabolismo , Proteínas Recombinantes/genética , Fenilalanina , Aminoacil-ARNt Sintetasas/metabolismo
11.
Front Immunol ; 14: 1307392, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38264661

RESUMEN

Introduction: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Anti-B-cell-activating factor (BAFF) therapy effectively depletes B cells and reduces SLE disease activity. This research aimed to evaluate the effect of BAFF blockade on B cell receptor (BCR) repertoire and gene expression. Methods: Through next-generation sequencing, we analyzed gene expression and BCR repertoire in MRL/lpr mice that received long-term anti-BAFF therapy. Based on gene expression profiles, we predicted the relative proportion of immune cells using ImmuCellAI-mouse, validating our predictions via flow cytometry and FluoroSpot. Results: The loss of BCR repertoire diversity and richness, along with increased clonality and differential frequency distribution of the immunoglobulin heavy chain variable (IGHV) segment gene usage, were observed in BAFF-blockade mice. Meanwhile, the distribution of complementarity-determining region 3 (CDR3) length and CDR3 amino acid usage remained unaffected. BAFF blockade resulted in extensive changes in gene expression, particularly that of genes related to B cells and immunoglobulins. Besides, the tumor necrosis factor (TNF)-α responses and interferon (IFN)-α/γ were downregulated, consistent with the decrease in IFN-γ and TNF-α serum levels following anti-BAFF therapy. In addition, BAFF blockade significantly reduced B cell subpopulations and plasmacytoid dendritic cells, and caused the depletion of antibody-secreting cells. Discussion: Our comparative BCR repertoire and transcriptome analyses of MRL/lpr mice subjected to BAFF blockade provide innovative insights into the molecular pathophysiology of SLE.


Asunto(s)
Lupus Eritematoso Sistémico , Transcriptoma , Animales , Ratones , Ratones Endogámicos MRL lpr , Modelos Animales de Enfermedad , Interferón-alfa , Regiones Determinantes de Complementariedad , Receptores de Antígenos de Linfocitos B
12.
Biosensors (Basel) ; 12(9)2022 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-36140113

RESUMEN

Detecting residual nasopharyngeal carcinoma (rNPC) can be difficult because of the coexistence of occult tumours and post-chemoradiation changes, which poses a challenge for both radiologists and surgeons using current imaging methods. Currently, molecular imaging that precisely targets and visualises particular biomarkers in tumours may exceed the specificity and sensitivity of traditional imaging techniques, providing the potential to distinguish tumours from non-neoplastic lesions. Here, we synthesised a HER2/SR-BI-targeted tracer to efficiently position NPC and guide surgery in living mice. This bispecific tracer contained the following two parts: IRDye 800 CW, as an imaging reagent for both optical and optoacoustic imaging, and a fusion peptide (FY-35), as the targeting reagent. Both in vitro and in vivo tests demonstrated that the tracer had higher accumulation and longer retention (up to 48 h) in tumours than a single-targeted probe, and realised sensitive detection of tumours with a minimum size of 3.9 mm. By visualising the vascular network via a customised handheld optoacoustic scan, our intraoperative fluorescence molecular imaging system provides accurate guidance for intraoperative tumour resection. Integrating the advantages of both optical and optoacoustic scanning in an intraoperative image-guided system, this method holds promise for depicting rNPC and guiding salvage surgery.


Asunto(s)
Colorantes Fluorescentes , Neoplasias Nasofaríngeas , Animales , Ratones , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico por imagen , Neoplasias Nasofaríngeas/cirugía , Imagen Óptica/métodos , Péptidos
13.
Eur J Nucl Med Mol Imaging ; 49(13): 4427-4439, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35925443

RESUMEN

PURPOSE: Accurate identification of nodal status enables adequate neck irradiation for nasopharyngeal carcinoma (NPC). However, most conventional techniques are unable to pick up occult metastases, leading to underestimation of tumor extensions. Here we investigate the clinical significance of carbonic anhydrase IX (CAIX) in human NPC samples, and develop a CAIX-targeted imaging strategy to identify occult lymph node metastases (LNMs) and extranodal extension (ENE) in animal studies. METHODS: A total of 211 NPC samples are performed CAIX staining, and clinical outcomes are analyzed. The metastatic murine models are generated by foot pad injection of NPC cells, and a CAIX-targeted imaging agent (CAIX-800) is intravenously administered. We adopt fluorescence molecular tomography and ultrasonography (US)-guided spectroscopic photoacoustic (sPA) imaging to perform in vivo studies. Histological and immunohistochemical characterization are carried out via node-by-node analysis. RESULTS: For clinical samples, 90.1% (91/101) primary tumors, 73.3% (66/90) metastases, and 100% (20/20) local recurrences are CAIX positive. In metastases group, 84.7% (61/72) nodal metastases and 22.2% (4/18) organ metastases are CAIX positive. CAIX expression in primary tumors is significantly associated with NPC stage and prognosis. For animal studies, CAIX-800-based fluorescence imaging achieves 81.3% sensitivity and 93.8% specificity in detecting occult LNMs in vivo, with a minimum detectable diameter of 1.7 mm. Coupled with CAIX-800, US-guided sPA imaging could not only detect subcapsular deposits of metastatic cancer cells 2 weeks earlier than conventional techniques, but also successfully track pathological ENE. CONCLUSION: CAIX remarkably expresses in human NPCs and stratifies patient prognosis. In preclinical studies, CAIX-800-based imaging successfully identifies occult LNMs and tracks early stage of pathological ENE. This attractive method shows potential in clinic, allowing medical workers to longitudinally monitor nodal status and helping to reduce unnecessary nodal biopsy for patients with NPC. The schematic diagram for the study. CAIX, carbonic anhydrase IX; NPC, nasopharyngeal carcinoma; US, ultrasonography; sPA, spectroscopic photoacoustic.


Asunto(s)
Anhidrasas Carbónicas , Neoplasias Nasofaríngeas , Humanos , Ratones , Animales , Anhidrasa Carbónica IX/metabolismo , Carcinoma Nasofaríngeo/diagnóstico por imagen , Anhidrasas Carbónicas/análisis , Anhidrasas Carbónicas/metabolismo , Biomarcadores de Tumor/metabolismo , Pronóstico , Antígenos de Neoplasias/análisis , Metástasis Linfática , Neoplasias Nasofaríngeas/diagnóstico por imagen , Modelos Animales
14.
Drug Des Devel Ther ; 16: 1885-1896, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35747442

RESUMEN

Although tigecycline is widely used in clinical practice, its efficiency and optimal dosage regimens remain controversial. The purpose of this article was to help guide tigecycline dosing in different patient subpopulations through comparing the published population pharmacokinetic models of tigecycline, as well as summarizing and determining the potential covariates that markedly influence tigecycline pharmacokinetics. In this review, literature was systematically searched from the PubMed database from inception to March 2022. The articles focusing on population pharmacokinetics for tigecycline in healthy volunteers or patients were included; finally, a total of eight studies were included in this review. NONMEM methods were used in five studies to generate the population pharmacokinetic models. Tigecycline pharmacokinetics were mostly described by a two-compartment model in these included studies. Estimated clearance and volumes of distribution of tigecycline at steady state (Vss) varied widely in different target patient populations, with a range of 7.5-23.1 L/h and 212.7-1087.7 L, respectively. Body-weight and creatinine clearance were the most important predictors of clearance in these studies, while other predictors include age, gender, bilirubin and aspartate aminotransferase. In conclusion, this review showed the large variability of tigecycline population pharmacokinetics, which can provide guide dosing in different target populations. For clinicians, the individual dosing adjustment should be based not only on the indication and pathogen susceptibility but also on the potential important predictors. However, more studies were needed to confirm the necessity of modified dosage regimens in different patient subpopulations.


Asunto(s)
Antibacterianos , Modelos Biológicos , Antibacterianos/uso terapéutico , Peso Corporal , Bases de Datos Factuales , Humanos , Tigeciclina
15.
Bioorg Med Chem ; 66: 116810, 2022 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-35580538

RESUMEN

Prostate-specific membrane antigen (PSMA) is emerging as a promising target to specifically image prostate cancer. Dual-modality probe combining radionuclide imaging and near-infrared fluorescence navigation targeting PSMA would enable both the preoperative staging and intraoperative detection of the tumor lesions. To overcome one of the key barriers for achieving high contrast imaging at both early and late time points, we optimized the pharmacokinetics of dual-modality probes based on oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA inhibitors recently developed. Four dual-modality probes with variable hydrophilicity were synthesized and evaluated. They displayed good optical properties (λem max = 835 nm, QY = 0.67%-1.50%), high affinity to PSMA (Ki = 2.09 ± 1.71-4.15 ± 2.20 nM) and PSMA specific cellular uptake (0.48 ± 0.01% - 0.64 ± 0.04% IA/105 LNCaP cells) upon labeled with 68Ga. In vivo studies showed that [68Ga]Ga-P3 exhibited an optimum pharmacokinetic property with high specific tumor uptake (SUVmax = 1.88 ± 0.36, at 1 h) in medium level PSMA expressing 22Rv1 tumor model and high tumor-to-muscle ratio (12.56 ± 2.63, at 1 h). Specific fluorescence imaging could also be achieved with high contrast for later time points (tumor-to-background ratio = 11.63 ± 4.16 at 24 h). This study demonstrates that ODAP-Urea-based P3 has the potential for PET imaging and intraoperative optical imaging of prostate cancer.


Asunto(s)
Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Aminoácidos Diaminos , Línea Celular Tumoral , Radioisótopos de Galio , Glutamato Carboxipeptidasa II/metabolismo , Humanos , Masculino , Imagen Óptica/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Distribución Tisular , Urea
16.
Eur J Nucl Med Mol Imaging ; 49(8): 2693-2704, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35235005

RESUMEN

PURPOSE: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is emerging as an effective treatment option for metastatic castration-resistant prostate cancer (mCRPC). An imaging-based method to quantify early treatment responses can help to understand and optimize RLT. METHODS: We developed a self-triggered probe 2 targeting the colocalization of PSMA and caspase-3 for fluorescence imaging of RLT-induced apoptosis. RESULTS: The probe binds to PSMA potently with a Ki of 4.12 nM, and its fluorescence can be effectively switched on by caspase-3 with a Km of 67.62 µM. Cellular and in vivo studies demonstrated its specificity for imaging radiation-induced caspase-3 upregulation in prostate cancer. To identify the detection limit of our method, we showed that probe 2 could achieve 1.79 times fluorescence enhancement in response to 177Lu-RLT in a medium PSMA-expressing 22Rv1 xenograft model. CONCLUSION: Probe 2 can potently bind to PSMA, and the fluorescence signal can be sensitively switched on by caspase-3 both in vitro and in vivo. This method may provide an effective tool to investigate and optimize PSMA-RLT.


Asunto(s)
Lutecio , Neoplasias de la Próstata Resistentes a la Castración , Antígenos de Superficie , Caspasa 3 , Dipéptidos , Glutamato Carboxipeptidasa II , Compuestos Heterocíclicos con 1 Anillo , Humanos , Lutecio/uso terapéutico , Masculino , Imagen Óptica , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Resultado del Tratamiento
17.
Life (Basel) ; 12(2)2022 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-35207448

RESUMEN

B7-H3 plays an important role in tumor apoptosis, proliferation, adhesion, angiogenesis, invasion, migration, and evasion of immune surveillance. It is overexpressed in various human solid tumor tissues. In patients, B7-H3 overexpression correlates with advanced stages, poor clinical outcomes, and resistance to therapy. The roles of B7-H3 in tumor progression make it a potential candidate for targeted therapy. Here, we generated a mouse anti-human B7-H3 antibody and demonstrated its binding activity via Tongji University Suzhou Instituteprotein-based and cell-based assays. We then developed a novel format anti-B7-H3 × anti-CD3 bispecific antibody based on the antibody-binding fragment of the anti-B7-H3 antibody and single-chain variable fragment structure of anti-CD3 antibody (OKT3) and demonstrated that this bispecific antibody mediated potent cytotoxic activities against various B7-H3-positive tumor cell lines in vitro by improving T cell activation and proliferation. This bispecific antibody also demonstrated potent antitumor activity in humanized mice xenograft models. These results revealed that the novel anti-B7-H3 × anti-CD3 bispecific antibody has the potential to be employed in treatment of B7-H3-positive solid tumors.

18.
Breast Cancer Res Treat ; 191(1): 51-61, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34657203

RESUMEN

PURPOSE: Disitamab vedotin (RC48) is an HER2-directed antibody-drug conjugate, emerging as an effective strategy for cancer therapy, which not only enhances antitumor immunity in previous animal models but also improves clinical outcomes for patients such as with gastric cancer, urothelium carcinoma, and HER2 low-expressing breast cancer. Here, we explore the combination therapeutic efficacy of this novel HER2-targeting ADC with immune checkpoint inhibitors in a human HER2-expressing syngeneic breast cancer model. METHODS: The human HER2+ cancer cell line is constructed by stable transfection and individual clones were isolated by single-cell sorting. Flow cytometry was performed to determine its binding activity. Cytotoxic effect was determined using an MTT assay with the supplement of RC48. Human PD-1 transgenic mice were used to analyze the in vivo antitumor effects of the ADC and its combination therapy with PD-1/PD-L1 antibody. RESULTS: The combination of RC48 and PD-1/PD-L1 immune checkpoint inhibition significantly enhanced tumor suppression and antitumor immunity. Tumor rejection in the synergistic groups was accompanied by massive T cell infiltration and immune marker activation. Furthermore, the combination therapy promoted immunological memory formation in the tumor eradication animals, protecting them from tumor rechallenge. CONCLUSION: A novel HER2-targeting ADC combined with immune checkpoint inhibitors can achieve remarkable effects in mice and elicit long-lasting immune protection in a hHER2+ murine breast cancer model. This study provides insights into the efficacy of RC48 therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy.


Asunto(s)
Neoplasias de la Mama , Inmunoconjugados , Memoria Inmunológica , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Femenino , Humanos , Inmunoconjugados/farmacología , Ratones , Ratones Transgénicos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores
19.
Int Immunopharmacol ; 101(Pt B): 108199, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34673297

RESUMEN

Acquired resistance to the antitumor activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in various types of cancers has increasingly been observed during treatment. To gain insight into the molecular mechanism underlying anti-PD-1 therapy resistance, we developed a mouse MC38 colon adenocarcinoma cell line that was made resistant to anti-PD-1 treatment through repeated in vivo selection. We compared the transcriptomic profiles of anti-PD-1 therapy-resistant and -sensitive tumors using RNA sequencing analysis. The immunosuppressive molecule transmembrane glycoprotein NMB (GPNMB) was significantly upregulated in resistant tumor cells, as determined using quantitative real-time polymerase chain reaction and immunofluorescence analyses. Furthermore, deletion of GPNMB in resistant cells successfully restored sensitivity to anti-PD-1 treatment in vivo. Collectively, our results indicate that tumors may develop resistance to anti-PD-1 therapy by upregulating their expression of the immunosuppressive molecule GPNMB. Furthermore, GPNMB is a potential, targetable biomarker for monitoring adaptive resistance to therapeutic PD-1 blockade, and identification of this immunosuppressive molecule may be a breakthrough for new therapies.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Proteínas del Ojo/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Adaptación Fisiológica , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animales , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Proteínas del Ojo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Terapia de Inmunosupresión , Glicoproteínas de Membrana/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Neoplasias Experimentales , Receptor de Muerte Celular Programada 1/genética , Organismos Libres de Patógenos Específicos , Microambiente Tumoral , Regulación hacia Arriba , Valeratos
20.
Sensors (Basel) ; 21(17)2021 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-34502657

RESUMEN

For urban traffic, traffic accidents are the most direct and serious risk to people's lives, and rapid recognition and warning of traffic accidents is an important remedy to reduce their harmful effects. However, research scholars are often confronted with the problem of scarce and difficult-to-collect accident data resources for traffic accident scenarios. Therefore, in this paper, a traffic data generation model based on Generative Adversarial Networks (GAN) is developed. To make GAN applicable to non-graphical data, we improve the generator network structure of the model and used the generated model to resample the original data to obtain new traffic accident data. By constructing an adversarial neural network model, we generate a large number of data samples that are similar to the original traffic accident data. Results of the statistical test indicate that the generated samples are not significantly different from the original data. Furthermore, the experiments of traffic accident recognition with several representative classifiers demonstrate that the augmented data can effectively enhance the performance of accident recognition, with a maximum increase in accuracy of 3.05% and a maximum decrease in the false positive rate of 2.95%. Experimental results verify that the proposed method can provide reliable mass data support for the recognition of traffic accidents and road traffic safety.


Asunto(s)
Accidentes de Tránsito , Redes Neurales de la Computación , Humanos , Proyectos de Investigación
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