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1.
J Dermatolog Treat ; 35(1): 2355261, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38767401

RESUMO

BACKGROUND: Biologics have revolutionized psoriasis treatment; however, relapse of psoriasis after discontinuation of biologics remains unresolved. OBJECTIVE: To assess the impact of adjunctive Chinese medicine (CM) therapy on relapse of psoriasis vulgaris (PV) after discontinuation of biologics. METHODS: We constructed a prospective cohort study through a psoriasis case registry platform that enrolled patients treated with biologics (in combination with or without CM). The endpoint event was relapse, defined as loss of psoriasis area and severity index (PASI) 75. RESULTS: A total of 391 patients completed the study and were included in the analysis, of whom 169 (43.2%) experienced relapse during follow-up. To minimize the bias, a 1:1 propensity score matching (PSM) was performed, generating matched cohorts of 156 individuals per group. Adjuvant CM therapy significantly associated with reduced incidence of relapse (HR =0.418, 95% CI = 0.289 ∼ 0.604, p < 0.001), and the protective effect of CM in the subgroup analysis was significant. In addition, PASI 90 response and disease duration were associated with relapse (p < 0.05). CONCLUSION: Adjunctive CM therapy is associated with reduced relapse incidence in PV after discontinuation of biologics.


Assuntos
Produtos Biológicos , Psoríase , Recidiva , Sistema de Registros , Índice de Gravidade de Doença , Humanos , Psoríase/tratamento farmacológico , Psoríase/patologia , Masculino , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Adulto , Produtos Biológicos/uso terapêutico , Resultado do Tratamento , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa
2.
Transl Lung Cancer Res ; 13(4): 885-900, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38736487

RESUMO

Background: In the context of surgical interventions for lung adenocarcinoma (LADC), precise determination of the extent of LADC infiltration plays a pivotal role in shaping the surgeon's strategic approach to the procedure. The prevailing diagnostic standard involves the expeditious intraoperative pathological diagnosis of areas infiltrated by LADC. Nevertheless, current methodologies rely on the visual interpretation of tissue images by proficient pathologists, introducing an error margin of up to 15.6%. Methods: In this study, we investigated the utilization of Micro-Raman technique on isolated specimens of human LADC with the objective of formulating and validating a workflow for the pathological diagnosis of LADC featuring diverse degrees of infiltration. Our strategy encompasses a thorough pathological characterization of LADC, spanning different tissue types and levels of infiltration. Through the integration of Raman spectroscopy with advanced deep learning models for simultaneous diagnosis, this approach offers a swift, precise, and clinically relevant means of analysis. Results: The diagnostic performance of the convolutional neural network (CNN) model, coupled with the microscopic Raman technique, was found to be exceptional and consistent, surpassing the traditional support vector machine (SVM) model. The CNN model exhibited an area under the curve (AUC) value of 96.1% for effectively distinguishing normal tissue from LADC and an impressive 99.0% for discerning varying degrees of infiltration in LADCs. To comprehensively assess its clinical utility, Raman datasets from patients with intraoperative rapid pathologic diagnostic errors were utilized as test subjects and input into the established CNN model. The results underscored the substantial corrective capacity of the Micro-Raman technique, revealing a misdiagnosis correction rate exceeding 96% in all cases. Conclusions: Ultimately, our discoveries highlight the Micro-Raman technique's potential to augment the intraoperative diagnostic precision of LADC with varying levels of infiltration. And compared to the traditional SVM model, the CNN model has better generalization ability in diagnosing different infiltration levels. This method furnishes surgeons with an objective groundwork for making well-informed decisions concerning subsequent surgical plans.

4.
BMC Psychol ; 12(1): 257, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720377

RESUMO

OBJECTIVE: This study aimed to investigate the relationships between childhood maltreatment, shame, and self-esteem among juvenile female offenders and to explore the potential influencing factors on their criminal behavior. METHODS: Using a stratified cluster sampling method, 1,227 juvenile female offenders from 11 provinces in China were surveyed using the Childhood Trauma Questionnaire (CTQ), Self-Esteem Scale (SES), and a self-developed Shame Questionnaire for Juvenile Offenders. Data were analyzed using descriptive statistics, correlation analysis, chi-square tests, t-tests, and structural equation modeling with mediation analysis. RESULTS: (1) Childhood maltreatment have a significant potential influencing factors on criminal behavior; (2) Childhood maltreatment was positively correlated with self-esteem(ß = 0.351, p < 0.001); (3) shame (ß = 0.042, p < 0.001) mediate the relationship between Childhood maltreatment and self-esteem (childhood maltreatment → shame → self-esteem (95% Cl: 0.033, 0.052)). CONCLUSION: This study demonstrates that childhood maltreatment is a significant predictor of criminal behavior among juvenile female offenders. childhood maltreatment can directly influence of self-esteem, which can also affect juvenile female offenders'self-esteem indirectly through shame. The findings suggest that shame are important variables that mediate the effect of the juvenile female offenders'childhood maltreatment on their self-esteem.


Assuntos
Maus-Tratos Infantis , Comportamento Criminoso , Criminosos , Autoimagem , Vergonha , Feminino , Humanos , Adolescente , Maus-Tratos Infantis/psicologia , Maus-Tratos Infantis/estatística & dados numéricos , Criminosos/psicologia , Criminosos/estatística & dados numéricos , China , Inquéritos e Questionários , Delinquência Juvenil/psicologia , Delinquência Juvenil/estatística & dados numéricos , Criança
5.
Cancer Res ; 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38718305

RESUMO

Peripheral T cell lymphoma (PTCL) is a heterogeneous and aggressive disease with a poor prognosis. Histone deacetylase (HDAC) inhibitors have shown inhibitory effects on PTCL. A better understanding of the therapeutic mechanism underlying the effects of HDAC inhibitors could help improve treatment strategies. Here, we found that high expression of HDAC3 is associated with poor prognosis in PTCL. HDAC3 inhibition suppressed lymphoma growth in immunocompetent mice but not in immunodeficient mice. HDAC3 deletion delayed the progression of lymphoma, reduced the lymphoma burden in the thymus, spleen, and lymph nodes, and prolonged the survival of mice bearing MNU-induced lymphoma. Furthermore, inhibiting HDAC3 promoted the infiltration and enhanced the function of natural killer (NK) cells. Mechanistically, HDAC3 mediated ATF3 deacetylation, enhancing its transcriptional inhibitory activity. Targeting HDAC3 enhanced CXCL12 secretion through an ATF3-dependent pathway to stimulate NK cell recruitment and activation. Finally, HDAC3 suppression improved the response of PTCL to conventional chemotherapy. Collectively, this study provides insights into the mechanism by which HDAC3 regulates ATF3 activity and CXCL12 secretion, leading to immune infiltration and lymphoma suppression. Combining HDAC3 inhibitors with chemotherapy may be a promising strategy for treating PTCL. Key words: Histone deacetylases (HDACs), Natural killer (NK) cells, Peripheral T cell lymphoma (PTCL).

6.
BMC Cancer ; 24(1): 448, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605339

RESUMO

BACKGROUND: Whole-mount histopathology (WMH) has been a powerful tool to investigate the characteristics of prostate cancer. However, the latest advancement of WMH was yet under summarization. In this review, we offer a comprehensive exposition of current research utilizing WMH in diagnosing and treating prostate cancer (PCa), and summarize the clinical advantages of WMH and outlines potential on future prospects. METHODS: An extensive PubMed search was conducted until February 26, 2023, with the search term "prostate", "whole-mount", "large format histology", which was limited to the last 4 years. Publications included were restricted to those in English. Other papers were also cited to contribute a better understanding. RESULTS: WMH exhibits an enhanced legibility for pathologists, which improved the efficacy of pathologic examination and provide educational value. It simplifies the histopathological registration with medical images, which serves as a convincing reference standard for imaging indicator investigation and medical image-based artificial intelligence (AI). Additionally, WMH provides comprehensive histopathological information for tumor volume estimation, post-treatment evaluation, and provides direct pathological data for AI readers. It also offers complete spatial context for the location estimation of both intraprostatic and extraprostatic cancerous region. CONCLUSIONS: WMH provides unique benefits in several aspects of clinical diagnosis and treatment of PCa. The utilization of WMH technique facilitates the development and refinement of various clinical technologies. We believe that WMH will play an important role in future clinical applications.


Assuntos
Inteligência Artificial , Neoplasias da Próstata , Masculino , Humanos , Imageamento por Ressonância Magnética/métodos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Próstata/patologia
7.
Phys Chem Chem Phys ; 26(16): 12709-12716, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38605665

RESUMO

The electronic structures and elastic properties of metastable Zr3N4 phases have been investigated using the first-principles calculations with the Heyd-Scuseria-Ernzerhof (HSE06) hybrid functional, in comparison with those of the stable ZrN phase. All three metastable Zr3N4 phases (including orthorhombic, spinel and Th3P4-type phases) are found to be semiconducting with bandgaps of 1.72-1.94 eV. In particular, the computationally indirect bandgap of 1.72 eV of orthorhombic Zr3N4 is consistent with the experimental value of 1.8 eV. The detailed analyses of the electronic structures reveal that the change of electrical conductivity from metallic ZrN to semiconducting Zr3N4 is mainly due to the electron transfer from Zr to N atoms, which weakens the Zr-Zr interactions and reduces the proportion of metallic bonding. In addition, the elastic properties of Zr3N4 and ZrN phases have been calculated. The theoretical hardness values of ZrN and orthorhombic Zr3N4 are 18.06 and 6.98 GPa, respectively, agreeing well with the experimental values of 19.26 and 7.90 GPa. This work may further promote the understanding of the promising Zr-N material system.

8.
Int J Biol Macromol ; 268(Pt 1): 131744, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38663711

RESUMO

Herpetrione(HPE) is an effective compound that has been used in the treatment of liver diseases. To improve its dissolution and absorption, herpetrione nanosuspensions was prepared. Nanosuspensions were proved to achieve intact absorption in vivo. However, the transport mechanisms are not fully understood, especially lack of direct evidence of translocation of particulates. In this study, an environment-responsive dye, P4, was loaded into herpetrione amorphous nanoparticles (HPE-ANPs) to elucidate the absorption and transport mechanism of the nanoparticles. And the amount of HPE and nanoparticles in the samples were quantified using HPLC/LC-MS/MS and IVIS with the model of Caco-2 and Caco-2/HT29-MTX. Results demonstrated that HPE is mainly taken up by passive diffusion in the form of free drugs, while HPE-ANPs are internalized by an energy dependent active transport pathway or intracellular endocytosis. It is speculated that HPE-ANPs may change the original entry pathway of drug molecules. Furthermore, the presence of mucus layer and the use of HPMC E15 may contribute to drug absorption to some extent. Transcellular transport study indicates that HPE-ANPs has a poor absorption. In conclusion, the differences in the absorption behavior trends of HPE-ANPs are caused by the difference in particle properties and the form of existence of the drug.


Assuntos
Derivados da Hipromelose , Nanopartículas , Nanopartículas/química , Humanos , Células CACO-2 , Derivados da Hipromelose/química , Portadores de Fármacos/química , Transporte Biológico
9.
Hum Pathol ; 148: 32-40, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38670237

RESUMO

This study investigated the clinicopathological, immunohistochemical, and molecular features of primary leptomeningeal melanocytic neoplasms (LMNs). Twelve LMN cases were retrospectively reviewed. We performed Fluorescence in-situ hybridization (including a 4-probe FISH assay with CDKN2A and MYC assay) and Next-Generation sequencing analyses on available cases. Histologically, 2 tumours were classified as melanocytomas (MC), 2 as intermediate-grade melanocytomas (IMC), and 8 as leptomeningeal melanomas (LMM). Two rare cases of LMM were associated with large plaque-like blue nevus. One MC case was associated with Ota. Ten cases (83.3%) showed melanocytic cells with benign features diffusely proliferating within the meninges. The Ki-67 in three categories differed (MC 0-1%, IMC 0-3%, LMM 3-10%). 57.1% of LMM cases (4/7) were positive for FISH. Nine of 10 tumours harboured activating hotspot mutations in GNAQ, GNA11, or PLCB4. Additional mutations of EIF1AX, SF3B1, or BAP1 were found in 40%, 30%, and 10% of tumours, respectively. During the follow-up (median = 43 months), 5 LMM patients experienced recurrence and/or metastasis, 3 of them died of the disease and the other 2 are alive with the tumour. Our study is by far the first cohort of LMN cases tested by FISH. In addition to morphological indicators including necrosis and mitotic figures, using a combination of Ki-67 and FISH helps to differentiate between IMC and LMM, especially in LMM cases with less pleomorphic features. SF3B1 mutation is first described in 2 cases of plaque-type blue nevus associated with LMM. Patients with SF3B1 mutation might be related to poor prognosis in LMN.

10.
Nanomaterials (Basel) ; 14(8)2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38668182

RESUMO

There is much interest regarding the "coupled ferroelectricity and superconductivity" in the two-dimensional material, bilayer Td-MoTe2; however, the value and the type of electric polarization are unknown. The device structure and the measurement method show that the measured material is the composite of the pseudo-bilayer quantum Hall system, with a thickness of about thirty-six nanometers. The derived dielectric hysteresis loops and the calculated electronic structure reveal that the condensed large polarons are responsible for the reverse ferroelectricity and the coupled superconductivity. The maximum value of polaron-type electric polarization is ~12 nC/µm2 or 1.2 × 104 µc/cm2.

11.
Regen Biomater ; 11: rbae020, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38529352

RESUMO

Posterior capsule opacification (PCO) remains the predominant complication following cataract surgery, significantly impairing visual function restoration. In this study, we developed a PCO model that closely mimics the anatomical structure of the crystalline lens capsule post-surgery. The model incorporated a threaded structure for accurate positioning and observation, allowing for opening and closing. Utilizing 3D printing technology, a stable external support system was created using resin material consisting of a rigid, hollow base and cover. To replicate the lens capsule structure, a thin hydrogel coating was applied to the resin scaffold. The biocompatibility and impact on cellular functionality of various hydrogel compositions were assessed through an array of staining techniques, including calcein-AM/PI staining, rhodamine staining, BODIPY-C11 staining and EdU staining in conjunction with transwell assays. Additionally, the PCO model was utilized to investigate the effects of eight drugs with anti-inflammatory and anti-proliferative properties, including 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), THZ1, sorbinil, 4-octyl itaconate (4-OI), xanthohumol, zebularine, rapamycin and caffeic acid phenethyl ester, on human lens epithelial cells (HLECs). Confocal microscopy facilitated comprehensive imaging of the PCO model. The results demonstrated that the GelMA 60 5% + PLMA 2% composite hydrogel exhibited superior biocompatibility and minimal lipid peroxidation levels among the tested hydrogels. Moreover, compared to using hydrogel as the material for 3D printing the entire model, applying surface hydrogel spin coating with parameters of 2000 rpm × 2 on the resin-based 3D printed base yielded a more uniform cell distribution and reduced apoptosis. Furthermore, rapamycin, 4-OI and AICAR demonstrated potent antiproliferative effects in the drug intervention study. Confocal microscopy imaging revealed a uniform distribution of HLECs along the anatomical structure of the crystalline lens capsule within the PCO model, showcasing robust cell viability and regular morphology. In conclusion, the PCO model provides a valuable experimental platform for studying PCO pathogenesis and exploring potential therapeutic interventions.

12.
ACS Sens ; 9(3): 1178-1187, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38437216

RESUMO

Undoubtedly, a deep understanding of PM2.5-induced tumor metastasis at the molecular level can contribute to improving the therapeutic effects of related diseases. However, the underlying molecular mechanism of fine particle exposure through long noncoding RNA (lncRNA) regulation in autophagy and, ultimately, lung cancer (LC) metastasis remains elusive; on the other hand, the related monitoring sensor platform used to investigate autophagy and cell migration is lacking. Herein, this study performed an air-liquid interface microfluidic monitoring sensor (AIMMS) platform to analyze human bronchial epithelial cells after PM2.5 stimulation. The multiomics analysis [RNA sequencing (RNA-seq) on lncRNA and mRNA expressions separately] showed that MALAT1 was highly expressed in the PM2.5 treatment group. Furthermore, RNA-seq analysis demonstrated that autophagy-related pathways were activated. Notably, the main mRNAs associated with autophagy regulation, including ATG4D, ATG12, ATG7, and ATG3, were upregulated. Inhibition or downregulation of MALAT1 inhibited autophagy via the ATG4D/ATG12/ATG7/ATG3 pathway after PM2.5 exposure and ultimately suppressed LC metastasis. Thus, based on the AIMMS platform, we found that MALAT1 might become a promising therapeutic target. Furthermore, this low-cost AIMMS system as a fluorescence sensor integrated with the cell-monitor module could be employed to study LC migration after PM2.5 exposure. With the fluorescence cell-monitoring module, the platform could be used to observe the migration of LC cells and construct the tumor metastasis model. In the future, several fluorescence probes, including nanoprobes, could be used in the AIMMS platform to investigate many other biological processes, especially cell interaction and migration, in the fields of toxicology and pharmacology.


Assuntos
Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Microfluídica , Neoplasias Pulmonares/genética , Material Particulado/toxicidade , Autofagia
13.
Lab Chip ; 24(8): 2280-2286, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38506153

RESUMO

Concentration gradient generation and mixed combinations of multiple solutions are of great value in the field of biomedical research. However, existing concentration gradient generators for single or two-drug solutions cannot simultaneously achieve multiple concentration gradient formations and mixed solution combinations. Furthermore, the whole system was huge, and required expensive auxiliary equipment, which may lead to complex operations. To address this problem, we devised a novel 3D microchannel network design, which is capable of creating all the desired mixture combinations and concentration gradients of given small amounts of the input solutions. As a proof of concept, the device we presented was verified by both colorimetric and fluorescence detection methods to test the efficiency. This can enable the implementation of one to three solutions with no driving pump and facilitate unique multiple types of more concentration gradients and mixture combinations in a single operation. We envision that this will be a promising candidate for the development of simplified methods for screening of the appropriate concentration and combination, such as various drug screening applications.


Assuntos
Técnicas Analíticas Microfluídicas , Microfluídica , Avaliação Pré-Clínica de Medicamentos
14.
Cancer Imaging ; 24(1): 33, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38439101

RESUMO

OBJECTIVES: To differentiate benign and malignant solitary pulmonary lesions (SPLs) by amide proton transfer-weighted imaging (APTWI), mono-exponential model DWI (MEM-DWI), stretched exponential model DWI (SEM-DWI), and 18F-FDG PET-derived parameters. METHODS: A total of 120 SPLs patients underwent chest 18F-FDG PET/MRI were enrolled, including 84 in the training set (28 benign and 56 malignant) and 36 in the test set (13 benign and 23 malignant). MTRasym(3.5 ppm), ADC, DDC, α, SUVmax, MTV, and TLG were compared. The area under receiver-operator characteristic curve (AUC) was used to assess diagnostic efficacy. The Logistic regression analysis was used to identify independent predictors and establish prediction model. RESULTS: SUVmax, MTV, TLG, α, and MTRasym(3.5 ppm) values were significantly lower and ADC, DDC values were significantly higher in benign SPLs than malignant SPLs (all P < 0.01). SUVmax, ADC, and MTRasym(3.5 ppm) were independent predictors. Within the training set, the prediction model based on these independent predictors demonstrated optimal diagnostic efficacy (AUC, 0.976; sensitivity, 94.64%; specificity, 92.86%), surpassing any single parameter with statistical significance. Similarly, within the test set, the prediction model exhibited optimal diagnostic efficacy. The calibration curves and DCA revealed that the prediction model not only had good consistency but was also able to provide a significant benefit to the related patients, both in the training and test sets. CONCLUSION: The SUVmax, ADC, and MTRasym(3.5 ppm) were independent predictors for differentiation of benign and malignant SPLs, and the prediction model based on them had an optimal diagnostic efficacy.


Assuntos
Fluordesoxiglucose F18 , Prótons , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Amidas
15.
Opt Express ; 32(5): 6963-6976, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38439389

RESUMO

Polarization modulation of electromagnetic waves plays an important role in the field of optics and optoelectronics. Current polarization optics are typically limited to the modulation in a single transverse plane. However, manipulating polarization along the longitudinal direction is also important for full-space polarization modulation. Here, we propose two kinds of all-dielectric terahertz metasurfaces for longitudinally spatial polarization manipulation. The metasurfaces are capable of controlling polarization along the propagation path, namely: i) a longitudinal bifocal metalens with different polarization states at each focal point, and ii) a versatile metalens can simultaneously generate a uniformly polarized focused beam and a vector beam with varying polarization along the propagation path. Furthermore, the measurement of the dielectric thickness is demonstrated based on the polarization modulation feature of the metalens. The proposed metasurfaces allow for effective polarization state alteration along the propagation path, exhibiting significant potential for applications in versatile light-matter interactions, optical communications, and quantum optics.

16.
Adv Mater ; 36(19): e2311964, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38302097

RESUMO

CRISPR-Cas13 holds substantial promise for tissue repair through its RNA editing capabilities and swift catabolism. However, conventional delivery methods fall short in addressing the heightened inflammatory response orchestrated by macrophages during the acute stages of tendon injury. In this investigation, macrophage-targeting cationic polymers are systematically screened to facilitate the entry of Cas13 ribonucleic-protein complex (Cas13 RNP) into macrophages. Notably, SPP1 (OPN encoding)-producing macrophages are recognized as a profibrotic subtype that emerges during the inflammatory stage. By employing ROS-responsive release mechanisms tailored for macrophage-targeted Cas13 RNP editing systems, the overactivation of SPP1 is curbed in the face of an acute immune microenvironment. Upon encapsulating this composite membrane around the tendon injury site, the macrophage-targeted Cas13 RNP effectively curtails the emergence of injury-induced SPP1-producing macrophages in the acute phase, leading to diminished fibroblast activation and mitigated peritendinous adhesion. Consequently, this study furnishes a swift RNA editing strategy for macrophages in the inflammatory phase triggered by ROS in tendon injury, along with a pioneering macrophage-targeted carrier proficient in delivering Cas13 into macrophages efficiently.


Assuntos
Sistemas CRISPR-Cas , Macrófagos , Traumatismos dos Tendões , Macrófagos/metabolismo , Animais , Camundongos , Traumatismos dos Tendões/terapia , Traumatismos dos Tendões/genética , Imunoterapia , Edição de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células RAW 264.7 , Osteopontina/genética , Osteopontina/metabolismo , Espécies Reativas de Oxigênio/metabolismo
17.
Oncogene ; 43(10): 744-757, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38243079

RESUMO

Androgen receptors (ARs) play key roles in prostate cancer (PCa) progression and castration-resistant prostate cancer (CRPC) resistance to drug therapy. SET and MYND domain containing protein 2 (SMYD2), a lysine methyltransferase, has been reported to promote tumors by transcriptionally methylating important oncogenes or tumor repressor genes. However, the role of SMYD2 in CRPC drug resistance remains unclear. In this study, we found that SMYD2 expression was significantly upregulated in PCa tissues and cell lines. High SMYD2 expression indicated poor CRPC-free survival and overall survival in patients. SMYD2 knockdown dramatically inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) potential of 22Rv1 and C4-2 cells. Conversely, ectopic overexpression of SMYD2 promoted these effects in 22Rv1 and C4-2 cells. Mechanistically, SMYD2 methylated and phosphorylated ARs to affect AR ubiquitination and proteasome degradation, which further alters the AR transcriptome in CRPC cells. Importantly, the SMYD2 inhibitor AZ505 had a synergistic therapeutic effect with enzalutamide in CRPC cells and mouse models; however, it could also re-sensitize resistant CRPC cells to enzalutamide. Our findings demonstrated that SMYD2 enhances the methylation and phosphorylation of ARs and affects AR ubiquitination and proteasome degradation to modulate CRPC cell resistance to enzalutamide, indicating that SMYD2 serves as a crucial oncogene in PCa and is an ideal therapeutic target for CRPC.


Assuntos
Benzamidas , Lisina , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Animais , Camundongos , Masculino , Humanos , Receptores Androgênicos/genética , Metiltransferases , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Complexo de Endopeptidases do Proteassoma , Histona-Lisina N-Metiltransferase/genética
18.
Biomed Pharmacother ; 171: 116203, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38280330

RESUMO

Tumor immunotherapy, an innovative anti-cancer therapy, has showcased encouraging outcomes across diverse tumor types. Among these, the PD-1/PD-L1 signaling pathway is a well-known immunological checkpoint, which is significant in the regulation of immune evasion by tumors. Nevertheless, a considerable number of patients develop resistance to anti-PD-1/PD-L1 immunotherapy, rendering it ineffective in the long run. This research focuses on exploring the factors of PD-1/PD-L1-mediated resistance in tumor immunotherapy. Initially, the PD-1/PD-L1 pathway is characterized by its role in facilitating tumor immune evasion, emphasizing its role in autoimmune homeostasis. Next, the primary mechanisms of resistance to PD-1/PD-L1-based immunotherapy are analyzed, including tumor antigen deletion, T cell dysfunction, increased immunosuppressive cells, and alterations in the expression of PD-L1 within tumor cells. The possible ramifications of altered metabolism, microbiota, and DNA methylation on resistance is also described. Finally, possible resolution strategies for dealing with anti-PD-1/PD-L1 immunotherapy resistance are discussed, placing particular emphasis on personalized therapeutic approaches and the exploration of more potent immunotherapy regimens.


Assuntos
Neoplasias , Evasão Tumoral , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/metabolismo , Neoplasias/tratamento farmacológico , Imunoterapia , Microambiente Tumoral
20.
Transpl Immunol ; 82: 101922, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37657691

RESUMO

INTRODUCTION: The preoperative examination of kidney transplantation includes HLA antibody screening to initially determine the presence of preexisting donor-specific antibody (DSA) that mediates hyperacute rejection. Recipients with positive HLA antibodies require further HLA specificity analysis to type the antigen and determine the antigen mismatches between the donor and recipient. However, recipients with suspected antibodies would have no further HLA specificity analysis. It is unclear whether suspected HLA antibodies would affect renal graft function. This study aimed to explore the impact of pretransplant suspected HLA antibody on the long-term outcome of the graft kidney and thus determine the necessity of routinely performing the HLA specificity analysis in recipients with suspected HLA antibodies preoperatively. METHODS: This is a single-center retrospective cohort study. 179 kidney transplant recipients (KTRs) were included and further divided into HLA antibody-negative group (Group 1) and HLA antibody-suspected groups (Group 2) based on the result of the pretransplant HLA antibody screen test. And the antibody-suspected group was further divided into a low-mismatched group (Group A) and a high-mismatched group (Group B) according to the HLA specificity analysis. We tracked the renal function indexes, biochemical indexes, and posttransplant adverse events within 5 years after transplantation and explored the necessity of further HLA specificity analysis in recipients with pretransplant suspected HLA antibodies. RESULTS: There was no statistically significant difference in demographics between HLA antibody-negative group and HLA antibody-suspected groups. At 5 years of follow-up, the KTRs in HLA antibody-negative group had significantly higher eGFR levels, lower serum creatinine levels, and less urinary protein compared to those in antibody-suspected group. Meanwhile, the KTRs in low-mismatched group also had significantly higher eGFR levels, lower serum creatinine levels, and less proteinuria compared to those in high-mismatched group. Correlation analysis showed that the age of KTRs, urinary protein levels and the load capacity of HLA mismatches were associated with eGFR levels of KTRs at 5 year posttransplant. CONCLUSION: KTRs with suspected HLA antibodies before kidney transplantation have worse graft function than the preoperative HLA antibody-negative recipients in the long-term posttransplant follow-up. The specific load capacity of HLA mismatches, the age of the recipient and the urinary protein was found to be negatively correlated with long-term posttransplant renal outcomes. It is necessary to undergo further HLA specificity analysis for recipients with suspected HLA antibodies in HLA antibody screen test to explicit HLA mismatches and improve long-term posttransplant outcomes.


Assuntos
Anticorpos , Antígenos HLA , Humanos , Estudos Retrospectivos , Creatinina , Rim , Rejeição de Enxerto , Sobrevivência de Enxerto
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