Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.865
Filtrar
1.
Nat Genet ; 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627596

RESUMO

Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFß in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.

2.
Chem Commun (Camb) ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38628069

RESUMO

To avoid the unexpected aggregation and reduce the cytotoxicity of nanomaterials as optical probes in cell imaging applications, we propose a programmed DNA-cube as a carrier for silver nanoparticles (Ag NPs) to construct a specific hydrogen sulfide (H2S) responsive platform (Ag NP@DNA-cube) for diagnosing colorectal cancer (CRC) in this study. The DNA-cube maintains good dispersion of Ag NPs while providing excellent biocompatibility. Based on the characteristic overexpression of endogenous H2S in CRC cells, the Ag NPs are etched by H2S within target cells into silver sulfide quantum dots, thereby selectively illuminating the target cells. The Ag NP@DNA-cube exhibits a specific fluorescence response to CRC cells and achieves satisfactory imaging.

3.
Anal Chem ; 96(15): 5735-5740, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38567982

RESUMO

Lipid metabolic alterations are known to play a crucial role in cancer metastasis. As a key hub in lipid metabolism, intracellular neutral lipid accumulation in lipid droplets (LDs) has become a signature of aggressive human cancers. Nevertheless, it remains unclear whether lipid accumulation displays distinctive features in metastatic lesions compared to the primary ones. Here, we integrated multicolor stimulated Raman scattering (SRS) imaging with confocal Raman spectroscopy on the same platform to quantitatively analyze the amount and composition of LDs in intact human thyroid tissues in situ without any processing or labeling. Inspiringly, we found aberrant accumulation of triglycerides (TGs) in lymphatic metastases but not in normal thyroid, primary papillary thyroid carcinoma (PTC), or normal lymph node. In addition, the unsaturation degree of unsaturated TGs was significantly higher in the lymphatic metastases from patients diagnosed with late-stage (T3/T4) PTC compared to those of patients diagnosed with early-stage (T1/T2) PTC. Furthermore, both public sequencing data analysis and our RNA-seq transcriptomic experiment showed significantly higher expression of alcohol dehydrogenase-1B (ADH1B), which is critical to lipid uptake and transport, in lymphatic metastases relative to the primary ones. In summary, these findings unravel the lipid accumulation as a novel marker and therapeutic target for PTC lymphatic metastasis that has a poor response to the regular radioactive iodine therapy.


Assuntos
Carcinoma Papilar , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide , Metástase Linfática , Neoplasias da Glândula Tireoide/metabolismo , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/patologia , Radioisótopos do Iodo , Microscopia Óptica não Linear , Lipídeos
4.
Nano Lett ; 24(15): 4528-4536, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38573311

RESUMO

Enzymes in nature efficiently catalyze chiral organic molecules by elaborately tuning the geometrical arrangement of atoms in the active site. However, enantioselective oxidation of organic molecules by heterogeneous electrocatalysts is challenging because of the difficulty in controlling the asymmetric structures of the active sites on the electrodes. Here, we show that the distribution of chiral kink atoms on high-index facets can be precisely manipulated even on single gold nanoparticles; and this enabled stereoselective oxidation of hydroxyl groups on various sugar molecules. We characterized the crystallographic orientation and the density of kink atoms and investigated their specific interactions with the glucose molecule due to the geometrical structure and surface electrostatic potential.

5.
Zhongguo Zhong Yao Za Zhi ; 49(3): 717-727, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621875

RESUMO

Transcriptome sequencing was employed to mine the simple sequence repeat(SSR) locus information of Saposhnikovia divaricata and design specific primers, which aimed to provide a basis for the research on the genetic diversity of S. divaricata germplasm resources. The seed purity, 1 000-seed weight, germination rate, and seed vigor were determined. MISA was used to obtain the SSR locus information from 12 606 unigene longer than 1 kb in the transcriptome database. Forty-three pairs of SSR primers designed in Primer 3 were used to analyze the polymorphism of 28 S. divaricata samples of different sources. The results showed that there were differences in the seed purity, 1 000-seed weight, germination rate, vigor, and seed length and width among S. divaricata samples of different sources. Particularly, the germination rate and seed vigor had significant differences, and HB-ZJK1, NMG-CF4, NMG-BT, NMG-HLE1, and NMG-CF2 had significantly higher 1 000-seed weight, germination rate, and seed vigor than the samples of other sources. Among the 86 233 unigene, 12 606(14.62%) unigene contained 15 958 SSR loci, with one SSR locus every 5 009 bp on average. The SSR loci were mainly single nucleotide and dinucleotide repeats, which were dominated by G/C and TC/AG, respectively. All the primers were screened by using 28 S. divaricata sample from different habitats, and the primers corresponding to the amplification products with clear bands and stable polymorphism were obtained. The clustering results of the biological characteristics and genetic diversity of the 28 S. divaricata samples were basically consistent, and the samples of the same origin(HB-AG1, HB-AG2, HB-ZJK1, and HB-ZJK2) generally gathered together and had close genetic relationship. The SSRs in S. divaricata transcriptome has high frequency, rich types, and high polymorphism, which provides candidate molecular markers for the germplasm identification, genetic map construction, and molecular-assisted breeding.


Assuntos
Apiaceae , Transcriptoma , Polimorfismo Genético , Repetições de Microssatélites/genética , Apiaceae/genética , Etiquetas de Sequências Expressas
6.
Phys Chem Chem Phys ; 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38623876

RESUMO

Highly unsaturated carbon chains are generated in combustion processes and electrical discharges, and are confirmed constituents of the interstellar medium. In hydrogen-rich environments smaller carbon clusters tend to exist as linear chains, capped on each end by hydrogen atoms. Although the HC2nH+ polyacetylene chains have been extensively characterized spectroscopically, the corresponding odd HC2n+1H+ chains have received far less attention. Here we use two-colour resonance enhanced photodissociation spectroscopy to measure electronic spectra for HC2n+1H+ (n = 2-6) chains contained in a cryogenically cooled quadrupole ion trap. The HC2n+1H+ chains are formed either top-down by ionizing and fragmenting pyrene molecules using pulsed 266 nm radiation, or bottom-up by reacting cyclic carbon cluster cations with acetylene. Ion mobility measurements confirm that the HC2n+1H+ species are linear, consistent with predictions from electronic structure calculations. The HC2n+1H+ electronic spectra exhibit three band systems in the visible/near infrared spectral range, which each shifts progressively to longer wavelength by ≈90 nm with the addition of each additional CC subunit. The strongest visible HC11H+ band has a wavelength (λ = 545.1 nm) and width (1.5 nm) that match the strong λ 5450 diffuse interstellar band (DIB). However, other weaker HC11H+ bands do not correspond to catalogued DIBs, casting doubt on the role of HC11H+ as a carrier for the λ 5450 DIB. There are no identifiable correspondences between catalogued DIBs and bands for the other HC2n+1H+ chains, allowing upper limits to be established for their column densities in diffuse interstellar clouds.

7.
Foods ; 13(7)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38611286

RESUMO

Rumexpatientia L. ×Rumextianshanicus A. Los (RRL), known as "protein grass" in China, was recognized as a new food ingredient in 2021. However, the cultivation and product development of RRL are still at an early stage, and no peptide research has been reported. In this study, two novel antioxidant peptides, LKPPF and LPFRP, were purified and identified from RRL and applied to H2O2-induced HepG2 cells to investigate their antioxidant properties. It was shown that 121 peptides were identified by ultrafiltration, gel filtration chromatography, and LC-MS/MS, while computer simulation and molecular docking indicated that LKPPF and LPFRP may have strong antioxidant properties. Both peptides were not cytotoxic to HepG2 cells at low concentrations and promoted cell growth, which effectively reduced the production of intracellular ROS and MDA, and increased cell viability and the enzymatic activities of SOD, GSH-Px, and CAT. Therefore, LKPPF and LPFRP, two peptides, possess strong antioxidant activity, which provides a theoretical basis for their potential as food additives or functional food supplements, but still need to be further investigated through animal models as well as cellular pathways.

8.
Foods ; 13(7)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38611360

RESUMO

To establish the safe and reproducible effects of cold plasma (CP) technology on food products, this study evaluated the gelatinization parameters, fatty acid profile, and hygroscopic properties of rice grains repeatedly treated with low-pressure radiofrequency (RF) helium CP (13.56 MHz, 140 Pa, 120 W-20s, 0-4 times, and 300 g sample). Compared with the untreated (zero times) sample, with an increase in CP treatment times from one to four on rice, the water contact angle and cooking time decreased, while the water absorption rate and freshness index increased, and the pH value remained unchanged. CP repeating treatments essentially had no effect on the gelatinization enthalpy, but significantly increased the peak temperature of gelatinization. From the pasting profile of rice that has been repeatedly CP treated, the peak, breakdown, and setback viscosities in flour paste decreased. CP repeating treatments on rice did not change the short-range molecular order of starch. Compared with the untreated sample, the first helium CP treatment maintained the content of C18:1n9c, C18:2n6c, and C18:3n3, but the second to fourth CP treatment significantly decreased contents of these fatty acids (FAs) as the C18:0 content increased. The first three CP treatments can increase the water and sucrose solvent retention capacity in rice flours. CP repeatedly treated rice first exhibits the similar monolayer water content and solid surface area of water sorption. Principal component analysis shows that contact angle, pasting parameters, and fatty acid profile in milled rice are quite sensitive to CP treatment. Results support that the effect of low-pressure RF 120W helium CP treatment 20 s on rice grains is perdurable, and the improvement of CP intermittent treatments on rice cooking and pasting properties is an added benefit, and the hygroscopic properties of rice was kept.

9.
Int J Cardiol ; : 132029, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38583590

RESUMO

BACKGROUND: Programmed cell death 1 (PD-1) inhibitors can induce various adverse reactions associated with immunity, of which cardiotoxicity is a serious complication. Limited research exists on the link between PD-1 inhibitor use and pericardial effusion (PE) occurrence and outcomes. METHODS: We conducted a retrospective study at the First Affiliated Hospital of Xi'an Jiaotong University from 2017 to 2019, comparing cancer patients who developed PE within 2 years after PD-1 inhibitor therapy to those who did not. Our primary outcome was the all-cause mortality rate at one year. We applied the Kaplan-Meier method for survival analysis. Multivariate logistic regression was utilized to identify PE risk factors, adjusting for potential confounders. RESULTS: A total of 91 patients were finally included, of whom 39 patients had PE. Compared to non-PE group, one-year all-cause mortality was nearly 5 times higher in PE group (64.10% vs. 13.46%, P < 0.001). Patients who developed PE within 2 years of taking PD-1 inhibitors were significantly associated with increased all-cause mortality compared with those who did not (HR: 6.26, 95%CI: 2.70-14.53, P < 0.001). Multivariable logistic regression showed that use of sintilimab (OR: 14.568, 95%CI: 3.431-61.857, P < 0.001), history of lung cancer (OR: 15.360, 95%CI: 3.276-72.017, P = 0.001), and history of hypocalcemia (OR: 7.076, 95%CI: 1.879-26.649, P = 0.004) were independent risk factors of PE development in patients received PD-1 inhibitors therapy. CONCLUSIONS: In cancer patients receiving PD-1 inhibitors, PE was associated with higher one-year mortality. Use of sintilimab, and history of lung cancer or hypocalcemia were linked to PE occurrence.

10.
Front Toxicol ; 6: 1377542, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38605940

RESUMO

Though the portfolio of medicines that are extending and improving the lives of patients continues to grow, drug discovery and development remains a challenging business on its best day. Safety liabilities are a significant contributor to development attrition where the costliest liabilities to both drug developers and patients emerge in late development or post-marketing. Animal studies are an important and influential contributor to the current drug discovery and development paradigm intending to provide evidence that a novel drug candidate can be used safely and effectively in human volunteers and patients. However, translational gaps-such as toxicity in patients not predicted by animal studies-have prompted efforts to improve their effectiveness, especially in safety assessment. More holistic monitoring and "digitalization" of animal studies has the potential to enrich study outcomes leading to datasets that are more computationally accessible, translationally relevant, replicable, and technically efficient. Continuous monitoring of animal behavior and physiology enables longitudinal assessment of drug effects, detection of effects during the animal's sleep and wake cycles and the opportunity to detect health or welfare events earlier. Automated measures can also mitigate human biases and reduce subjectivity. Reinventing a conservative, standardized, and traditional paradigm like drug safety assessment requires the collaboration and contributions of a broad and multi-disciplinary stakeholder group. In this perspective, we review the current state of the field and discuss opportunities to improve current approaches by more fully leveraging the power of sensor technologies, artificial intelligence (AI), and animal behavior in a home cage environment.

11.
Bioorg Chem ; 147: 107329, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38608410

RESUMO

By co-culturing two endophytic fungi (Chaetomium virescens and Xylaria grammica) collected from the medicinal and edible plant Smilax glabra Roxb. and analyzing them with MolNetEnhancer module on GNPS platform, seven undescribed chromone-derived polyketides (chaetoxylariones A-G), including three pairs of enantiomer ones (2a/2b, 4a/4b and 6a/6b) and four optical pure ones (1, 3, 5 and 7), as well as five known structural analogues (8-12), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray diffraction, 13C NMR calculation and DP4+ probability analyses, as well as the comparison of the experimental electronic circular dichroism (ECD) data. Structurally, compound 1 featured an unprecedented chromone-derived sulfonamide tailored by two isoleucine-derived δ-hydroxy-3-methylpentenoic acids via the acylamide and NO bonds, respectively; compound 2 represented the first example of enantiomeric chromone derivative bearing a unique spiro-[3.3]alkane ring system; compound 3 featured a decane alkyl side chain that formed an undescribed five-membered lactone ring between C-7' and C-10'; compound 4 contained an unexpected highly oxidized five-membered carbocyclic system featuring rare adjacent keto groups; compound 7 featured a rare methylsulfonyl moiety. In addition, compound 10 showed a significant inhibition towards SW620/AD300 cells with an IC50 value of PTX significantly decreased from 4.09 µM to 120 nM, and a further study uncovered that compound 10 could obviously reverse the MDR of SW620/AD300 cells.

12.
World Neurosurg ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38608811

RESUMO

BACKGROUND: Diagnosing early lumbar spondylolisthesis is challenging for many doctors because of the lack of obvious symptoms. Using deep learning (DL) models to improve the accuracy of X-ray diagnoses can effectively reduce missed and misdiagnoses in clinical practice. PURPOSE: This study aimed to use a two-stage deep learning model, the Res-SE-Net model with the YOLOv8 algorithm, to facilitate efficient and reliable diagnosis of early lumbar spondylolisthesis based on lateral X-ray image identification. METHODS: A total of 2,424 lumbar lateral radiographs of patients treated in the Beijing Tongren Hospital between January 2021 and September 2023 were obtained. The data were labeled and mutually identified by three orthopedic surgeons after reshuffling in a random order and divided into a training set, validation set, and test set in a ratio of 7:2:1. We trained two models for automatic detection of spondylolisthesis. YOLOv8 model was used to detect the position of lumbar spondylolisthesis, and the Res-SE-Net classification method was designed to classify the clipped area and determine whether it was lumbar spondylolisthesis. The model performance was evaluated using a test set and an external dataset. Finally, we compared model validation results with professional clinicians' evaluation. RESULTS: The model achieved promising results, with a high diagnostic accuracy of 92.3%, precision of 93.5%, and recall of 93.1% for spondylolisthesis detection on the test set, the area under the curve (AUC) value was 0.934. CONCLUSION: Our Two-stage deep learning model provides doctors with a reference basis for the better diagnosis and treatment of early lumbar spondylolisthesis.

13.
Nat Commun ; 15(1): 3284, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627386

RESUMO

The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. Twenty eight potent antibodies are isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5, SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of BA.4/5 mAbs culminating in total loss of function with recent XBB.1.5.70 variants containing the so-called 'FLip' mutations at positions 455 and 456. Interestingly, activity of some mAbs is regained on the recently reported variant BA.2.86.


Assuntos
Anticorpos Monoclonais , Complicações Pós-Operatórias , Humanos , Mutação , SARS-CoV-2/genética , Anticorpos Neutralizantes , Anticorpos Antivirais
14.
Plant Mol Biol ; 114(3): 47, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38632206

RESUMO

Natural Antisense Transcripts (NATs) are a kind of complex regulatory RNAs that play crucial roles in gene expression and regulation. However, the NATs in Cannabis Sativa L., a widely economic and medicinal plant rich in cannabinoids remain unknown. In this study, we comprehensively predicted C. sativa NATs genome-wide using strand-specific RNA sequencing (ssRNA-Seq) data, and validated the expression profiles by strand-specific quantitative reverse transcription PCR (ssRT-qPCR). Consequently, a total of 307 NATs were predicted in C. sativa, including 104 cis- and 203 trans- NATs. Functional enrichment analysis demonstrated the potential involvement of the C. sativa NATs in DNA polymerase activity, RNA-DNA hybrid ribonuclease activity, and nucleic acid binding. Finally, 18 cis- and 376 trans- NAT-ST pairs were predicted to produce 621 cis- and 5,679 trans- small interfering RNA (nat-siRNAs), respectively. These nat-siRNAs were potentially involved in the biosynthesis of cannabinoids and cellulose. All these results will shed light on the regulation of NATs and nat-siRNAs in C. sativa.

15.
ACS Appl Mater Interfaces ; 16(15): 18503-18521, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38570902

RESUMO

Biomaterials can induce an inflammatory response in surrounding tissues after implantation, generating and releasing reactive oxygen species (ROS), such as hydrogen peroxide (H2O2). The excessive accumulation of ROS may create a microenvironment with high levels of oxidative stress (OS), which subsequently accelerates the degradation of the passive film on the surface of titanium (Ti) alloys and affects their biological activity. The immunomodulatory role of macrophages in biomaterial osteogenesis under OS is unknown. This study aimed to explore the corrosion behavior and bone formation of Ti implants under an OS microenvironment. In this study, the corrosion resistance and osteoinduction capabilities in normal and OS conditions of the Ti-24Nb-4Zr-8Sn (wt %, Ti2448) were assessed. Electrochemical impedance spectroscopy analysis indicated that the Ti2448 alloy exhibited superior corrosion resistance on exposure to excessive ROS compared to the Ti-6Al-4V (TC4) alloy. This can be attributed to the formation of the TiO2 and Nb2O5 passive films, which mitigated the adverse effects of OS. In vitro MC3T3-E1 cell experiments revealed that the Ti2448 alloy exhibited good biocompatibility in the OS microenvironment, whereas the osteogenic differentiation level was comparable to that of the TC4 alloy. The Ti2448 alloy significantly alleviates intercellular ROS levels, inducing a higher proportion of M2 phenotypes (52.7%) under OS. Ti2448 alloy significantly promoted the expression of the anti-inflammatory cytokine, interleukin 10 (IL-10), and osteoblast-related cytokines, bone morphogenetic protein 2 (BMP-2), which relatively increased by 26.9 and 31.4%, respectively, compared to TC4 alloy. The Ti2448 alloy provides a favorable osteoimmune environment and significantly promotes the proliferation and differentiation of osteoblasts in vitro compared to the TC4 alloy. Ultimately, the Ti2448 alloy demonstrated excellent corrosion resistance and immunomodulatory properties in an OS microenvironment, providing valuable insights into potential clinical applications as implants to repair bone tissue defects.

16.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 42(2): 142-153, 2024 Apr 01.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38597074

RESUMO

Pregnancy is a special period for developing and treating oral diseases. Oral emergencies during pregnancy need to be handled appropriately. Changes in the physiological environments and personal habits of pregnant women increase susceptibility to some oral diseases. However, clinical treatment strategies are limited due to the need to ensure the safety of pregnant women and fetuses. Pregnant women should obtain oral health knowledge and enhance their awareness. Dentists should adhere to the principle of "prevention before pregnancy, controlling symptoms during pregnancy, and treating diseases after pregnancy" for different pregnancy periods. They should also formulate appropriate treatment plans to control emergencies, prevent disease progression, and avoid harmful effects on pregnant women by using the safest, simplest, and most effective strategies that avoid adverse effects on fetuses. Pregnant women and dentists should combine prevention and treatment while collaborating in maintaining oral health during pregnancy. This article focuses on the principles of treatment during pregnancy, and the treatment timing, clinical management, and treatment strategies of different diseases causing oral emergencies during pregnancy are reviewed.


Assuntos
Emergências , Doenças da Boca , Gravidez , Feminino , Humanos , Saúde Bucal , Doenças da Boca/prevenção & controle
17.
J Pharm Sci ; 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38561054

RESUMO

Sialic acid (SA) is crucial for protecting glycoproteins from clearance. Efmarodocokin alfa (IL-22Fc), a fusion protein agonist that links IL-22 to the crystallizable fragment (Fc) of human IgG4, contains 8 N-glycosylation sites and exhibits heterogeneous and variable terminal sialylation biodistribution. This presents a unique challenge for Pharmacokinetic (PK) and Pharmacodynamic (PD) analysis and cross-species translation. In this study, we sought to understand how varying SA levels and heterogeneous distribution contribute to IL-22Fc's complex PKPD properties. We initially used homogenous drug material with varying SA levels to examine PKPD in mice. Population PKPD analysis based on mouse data revealed that SA was a critical covariate simultaneously accounting for the substantial between subject variability (BSV) in clearance (CL), distribution clearance (CLd), and volume of distribution (Vd). In addition to the well-established mechanism by which SA inhibits ASGPR activity, we hypothesized a novel mechanism by which decrease in SA increases the drug uptake by endothelial cells. This decrease in SA, leading to more endothelial uptake, was supported by the neonatal Fc receptor (FcRn) dependent cell-based transcytosis assay. The population analysis also suggested in vivo EC50 (IL-22Fc stimulating Reg3ß) was independent on SA, while the in-vitro assay indicated a contradictory finding of SA-in vitro potency relationship. We created a mechanism based mathematical (MBM) PKPD model incorporating the decrease in SA mediated endothelial and hepatic uptake, and successfully characterized the SA influence on IL-22Fc PK, as well as the increased PK exposure being responsible for increased PD. Thereby, the MBM model supported that SA has no direct impact on EC50, aligning with the population PKPD analysis. Subsequently, using the MBM PKPD model, we employed 5 subpopulation simulations to reconstitute the heterogeneity of drug material. The simulation accurately predicted the PKPD of heterogeneously and variably sialylated drug in mouse, monkey and human. The successful prospective validation confirmed the MBM's ability to predict IL-22Fc PK across variable SA levels, homogenous to heterogeneous material, and across species (R2=0.964 for clearance prediction). Our model prediction suggests an average of 1 mol/mol SA increase leads to a 50% increase in drug exposure. This underlines the significance of controlling sialic acid levels during lot-to-lot manufacturing.

18.
Materials (Basel) ; 17(7)2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38612012

RESUMO

Ni60-WC coatings with different WC contents on the bucket tooth substrates were pre- pared using laser cladding technology. Their abrasive wear properties were assessed using the dry sand rubber wheel test system. The substrate and the hard-facing layer were tested for comparison. The results showed that the hardness of the Ni60-WC coatings increased with the increase in WC content. The wear resistance of the bucket tooth substrate was greatly improved by hard-facing and laser cladding Ni60-WC coatings. The wear rate of the hard-facing layer was reduced to 1/6 of that of the tooth substrate. The wear rate of the laser cladding coatings with 20-40 wt.% WC was similar to that of the hard-facing layer. It is worth mentioning that the wear rate of the coatings with 60-80 wt.% WC was only 1/4 of that of the hard-facing layer. Micro-cutting with surface plastic deformation was the main wear mechanism of the substrate to form narrow and deep furrows. The wear mechanism of the hard-facing layer was mainly plastic deformation with a wide groove, and the surface cracks promoted the removal of the material. The removal of the binder phase caused by micro-cutting was the main wear mechanism of the laser cladding Ni60-WC coatings. However, the hard phase of WC hinders micro-cutting and plastic deformation, which improves the wear resistance of the coating.

19.
J Nucl Med ; 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38604764

RESUMO

68Ga-labeled nanobody (68Ga-NC-BCH) is a single-domain antibody-based PET imaging agent. We conducted a first-in-humans study of 68Ga-NC-BCH for PET to determine its in vivo biodistribution, metabolism, radiation dosimetry, safety, and potential for quantifying claudin-18 isoform 2 (CLDN18.2) expression in gastrointestinal cancer patients. Methods: Initially, we synthesized the probe 68Ga-NC-BCH and performed preclinical evaluations on human gastric adenocarcinoma cell lines and xenograft mouse models. Next, we performed a translational study with a pilot cohort of patients with advanced gastrointestinal cancer on a total-body PET/CT scanner. Radiopharmaceutical biodistribution, radiation dosimetry, and the relationship between tumor uptake and CLDN18.2 expression were evaluated. Results: 68Ga-NC-BCH was stably prepared and demonstrated good radiochemical properties. According to preclinical evaluation,68Ga-NC-BCH exhibited rapid blood clearance, high affinity for CLDN18.2, and high specific uptake in CLDN18.2-positive cells and xenograft mouse models. 68Ga-NC-BCH displayed high uptake in the stomach and kidney and slight uptake in the pancreas. Compared with 18F-FDG, 68Ga-NC-BCH showed significant differences in uptake in lesions with different levels of CLDN18.2 expression. Conclusion: A clear correlation was detected between PET SUV and CLDN18.2 expression, suggesting that 68Ga-NC-BCH PET could be used as a companion diagnostic tool for optimizing treatments that target CLDN18.2 in tumors.

20.
Asian J Surg ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38604849

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly heterogeneous liver tumor. The associations between histopathological feature and prognosis of ICC are limited. The present study aimed to investigate the prognostic significance of glandular structure and tumor budding in ICC. METHODS: Patients received radical hepatectomy for ICC were included. Glandular structure and tumor budding were detected by Hematoxylin-eosin staining. The Kaplan-Meier method and the Cox proportional hazards regression model were used to calculate the survival and hazard ratio. Based on the results of multivariate analysis, nomograms of OS and DFS were constructed. C-index and Akaike information criterion (AIC) were used to assess accuracy of models. RESULTS: A total of 323 ICC patients who underwent surgery were included in our study. Glandular structure was associated with worse overall survival (OS) [hazard ratio (HR): 2.033, 95% confidence interval (CI): 1.047 to 3.945] and disease-free survival (DFS) [HR: 1.854, 95% CI: 1.082 to 3.176]. High tumor budding was associated with worse DFS [HR: 1.636, 95%CI: 1.060 to 2.525]. Multivariate analysis suggested that glandular structure, tumor number, lymph node metastasis, and CA19-9 were independent risk factors for OS. Independent predictor factors for DFS were tumor budding, glandular structure, tumor number, and lymph node metastasis. The c-index (0.641 and 0.642) and AIC (957.69 and 1188.52) showed that nomograms of OS and DFS have good accuracy. CONCLUSION: High tumor budding and glandular structure are two important histopathological features that serve as prognostic factors for ICC patients undergoing hepatectomy.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...