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1.
J Nat Prod ; 87(6): 1660-1665, 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38888514

RESUMEN

Chetocochliodin M (5) containing a rare cage-ring and chetocochliodin N (6) featuring an unusual piperazine-2,3-dione ring system together with known analogues chetomin (1), chetoseminudin C (2), chetocochliodin I (3), and oidioperazine E (4) were targeted for purification from the fungus Chaetomium cochliodes using a UPLC-Q-TOF-MS/MS approach. The structures of the new compounds were elucidated using HR-ESI-MS, NMR, and ECD spectra. Compounds 1, 3, and 6 exhibited strong cytotoxic activities against A549 and HeLa cancer cell lines.


Asunto(s)
Chaetomium , Espectrometría de Masas en Tándem , Chaetomium/química , Humanos , Estructura Molecular , Espectrometría de Masas en Tándem/métodos , Células HeLa , Cromatografía Líquida de Alta Presión/métodos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Células A549 , Piperazinas/farmacología , Piperazinas/química , Piperazinas/aislamiento & purificación
2.
Health Expect ; 27(2): e14039, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38613765

RESUMEN

OBJECTIVES: To identify, describe and synthesise the views and experiences of adults living with asthma regarding shared decision-making (SDM) in the existing qualitative literature METHODS: We conducted a comprehensive search of 10 databases (list databases) from inception until September 2023. Screening was performed according to inclusion criteria. Tools from the Joanna Briggs lnstitute were utilised for the purposes of data extraction and synthesis in this study. The data extraction process in this study employed the Capability, Opportunity and Motivation Model of Behaviour (COM-B model) as a framework, and a pragmatic meta-aggregative approach was employed to synthesise the collected results. RESULTS: Nineteen studies were included in the metasynthesis. Three synthesised themes were identified: the capability of people living with asthma, the opportunities of people living with asthma in SDM, and the motivation of the people living with asthma in SDM. CONCLUSIONS: We have identified specific factors influencing people living with asthma engaging in SDM. The findings of this study can serve as a basis for the implementation of SDM in people living with asthma and provide insights for the development of their SDM training programs. The ConQual score for the synthesised findings was rated as low. To enhance confidence, future studies should address dependability and credibility factors. PRACTICE IMPLICATIONS: This review contemplates the implementation of SDM from the perspective of people living with asthma, with the aim of providing patient-centred services for them. The results of this review can benefit the implementation of SDM and facilitate information sharing. It offers guidance for SDM skills training among adults living with asthma, fosters a better doctor-patient relationship and facilitates consensus in treatment decisions, thereby enabling personalised and tailored medical care. PATIENT OR PUBLIC CONTRIBUTION: Three nursing graduate students participated in the data extraction and integration process, with two students having extensive clinical experience that provided valuable insights for the integration.


Asunto(s)
Asma , Relaciones Médico-Paciente , Adulto , Humanos , Investigación Cualitativa , Asma/terapia , Consenso , Toma de Decisiones Conjunta
3.
Int J Biol Macromol ; 268(Pt 1): 131643, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38643918

RESUMEN

The rational design of hydrogel materials to modulate the immune microenvironment has emerged as a pivotal approach in expediting tissue repair and regeneration. Within the immune microenvironment, an array of immune cells exists, with macrophages gaining prominence in the field of tissue repair and regeneration due to their roles in cytokine regulation to promote regeneration, maintain tissue homeostasis, and facilitate repair. Macrophages can be categorized into two types: classically activated M1 (pro-inflammatory) and alternatively activated M2 (anti-inflammatory and pro-repair). By regulating the physical and chemical properties of hydrogels, the phenotypic transformation and cell behavior of macrophages can be effectively controlled, thereby promoting tissue regeneration and repair. A full understanding of the interaction between hydrogels and macrophages can provide new ideas and methods for future tissue engineering and clinical treatment. Therefore, this paper reviews the effects of hydrogel components, hardness, pore size, and surface morphology on cell behaviors such as macrophage proliferation, migration, and phenotypic polarization, and explores the application of hydrogels based on macrophage immune regulation in skin, bone, cartilage, and nerve tissue repair. Finally, the challenges and future prospects of macrophage-based immunomodulatory hydrogels are discussed.


Asunto(s)
Hidrogeles , Macrófagos , Regeneración , Cicatrización de Heridas , Hidrogeles/química , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Humanos , Animales , Regeneración/inmunología , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/inmunología , Ingeniería de Tejidos , Inmunomodulación/efectos de los fármacos
4.
Cancer Lett ; 588: 216776, 2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38432581

RESUMEN

Due to the limited effectiveness of current treatments, the survival rate of patients with metastatic castration-resistant prostate cancer (mCRPC) is significantly reduced. Consequently, it is imperative to identify novel therapeutic targets for managing these patients. Since the invasive ability of cells is crucial for establishing and maintaining metastasis, the aim of this study was to identify the essential regulators of invasive abilities of mCRPC cells by conducting two independent high-throughput CRISPR/Cas9 screenings. Furthermore, some of the top hits were validated using siRNA technology, with protein arginine methyltransferase 7 (PRMT7) emerging as the most promising candidate. We demonstrated that its inhibition or depletion via genetic or pharmacological approaches significantly reduces invasive, migratory and proliferative abilities of mCRPC cells in vitro. Moreover, we confirmed that PRMT7 ablation reduces cell dissemination in chicken chorioallantoic membrane and mouse xenograft assays. Molecularly, PRMT7 reprograms the expression of several adhesion molecules by methylating various transcription factors, such as FoxK1, resulting in the loss of adhesion from the primary tumor and increased motility of mCRPC cells. Furthermore, PRMT7 higher expression correlates with tumor aggressivity and poor overall survival in prostate cancer patients. Thus, this study demonstrates that PRMT7 is a potential therapeutic target and potential biomarker for mPCa.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Proteína-Arginina N-Metiltransferasas , Masculino , Animales , Ratones , Humanos , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Sistemas CRISPR-Cas , Genes Esenciales , Detección Precoz del Cáncer
5.
Heliyon ; 10(3): e25365, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38322868

RESUMEN

The establishment of a stable animal model for intrauterine adhesion (IUA) can significantly enhance research on the pathogenesis and pathological changes of this disease, as well as on the development of innovative therapeutic approaches. In this study, three different modeling methods, including phenol mucilage combined mechanical scraping, ethanol combined mechanical scraping and ethanol modeling alone were designed. The morphological characteristics of the models were evaluated. The underlying mechanisms and fertility capacity of the ethanol modeling group were analyzed and compared to those of the sham surgery group. All three methods resulted in severe intrauterine adhesions, with ethanol being identified as a reliable modeling agent and was subsequently subjected to further evaluation. Immunohistochemistry and RT-PCR results indicated that the ethanol modeling group exhibited an increase in the degree of fibrosis and inflammation, as well as a significant reduction in endometrial thickness, gland number, vascularization, and endometrial receptivity, ultimately resulting in the loss of fertility capacity. The aforementioned findings indicate that the intrauterine perfusion of 95 % ethanol is efficacious in inducing the development of intrauterine adhesions in rats. Given its cost-effectiveness, efficacy, and stability in IUA formation, the use of 95 % ethanol intrauterine perfusion may serve as a novel platform for evaluating innovative anti-adhesion materials and bioengineered therapies.

6.
Br J Cancer ; 130(7): 1109-1118, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38341511

RESUMEN

BACKGROUND: 13-15% of breast cancer/BC patients diagnosed as pathological complete response/pCR after neoadjuvant systemic therapy/NST suffer from recurrence. This study aims to estimate the rationality of organoid forming potential/OFP for more accurate evaluation of NST efficacy. METHODS: OFPs of post-NST residual disease/RD were checked and compared with clinical approaches to estimate the recurrence risk. The phenotypes of organoids were classified via HE staining and ER, PR, HER2, Ki67 and CD133 immuno-labeling. The active growing organoids were subjected to drug sensitivity tests. RESULTS: Of 62 post-NST BC specimens, 24 were classified as OFP-I with long-term active organoid growth, 19 as OFP-II with stable organoid growth within 3 weeks, and 19 as OFP-III without organoid formation. Residual tumors were overall correlated with OFP grades (P < 0.001), while 3 of the 18 patients (16.67%) pathologically diagnosed as tumor-free (ypT0N0M0) showed tumor derived-organoid formation. The disease-free survival/DFS of OFP-I cases was worse than other two groups (Log-rank P < 0.05). Organoids of OFP-I/-II groups well maintained the biological features of their parental tumors and were resistant to the drugs used in NST. CONCLUSIONS: The OFP would be a complementary parameter to improve the evaluation accuracy of NST efficacy of breast cancers.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Terapia Neoadyuvante , Supervivencia sin Enfermedad , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
7.
Protein Sci ; 33(3): e4904, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38358126

RESUMEN

UBE2T is an attractive target for drug development due to its linkage with several types of cancers. However, the druggability of ubiquitin-conjugating E2 (UBE2T) is low because of the lack of a deep and hydrophobic pocket capable of forming strong binding interactions with drug-like small molecules. Here, we performed fragment screening using 19 F-nuclear magnetic resonance (NMR) and validated the hits with 1 H-15 N-heteronuclear single quantum coherence (HSQC) experiment and X-ray crystallographic studies. The cocrystal structures obtained revealed the binding modes of the hit fragments and allowed for the characterization of the fragment-binding sites. Further screening of structural analogues resulted in the identification of a compound series with inhibitory effect on UBE2T activity. Our current study has identified two new binding pockets in UBE2T, which will be useful for the development of small molecules to regulate the function of this protein. In addition, the compounds identified in this study can serve as chemical starting points for the development of UBE2T modulators.


Asunto(s)
Enzimas Ubiquitina-Conjugadoras , Ubiquitina , Enzimas Ubiquitina-Conjugadoras/metabolismo , Sitios de Unión
8.
Appl Biochem Biotechnol ; 196(1): 573-587, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37160564

RESUMEN

Molecular-targeted therapies for lung squamous cell carcinoma (LSCC) are limited mainly because targetable oncogenic aberrations are absent in LSCC. Recent genomic analyses have revealed that the fibroblast growth factor (FGF) signaling pathway plays a fundamental role in LSCC progression via cancer cell proliferation and angiogenesis. In the present study, we designed, expressed, and purified a fibroblast growth factor receptor fragment (FGFR1-Fc) fusion protein using NS/0 cells. In FGF2-FGFR1 overexpressed NCI-H1703 cells, the FGFR1-Fc fusion protein effectively inhibited proliferation and invasion and arrested the cell cycle at the G0-G1 phase. In NCI-H1703 cells treated with the FGFR1-Fc fusion protein, the phosphorylation levels of FGFR1, FRS2, ERK, and AKT were significantly reduced. Using an siRNA assay, we demonstrated that FGF2-FGFR1 is the major anti-tumor target of FGFR1-Fc fusion the FGFR1-Fc fusion protein, which also significantly inhibited proliferation and invasion by NCI-H1703 cells via the FGF2-FGFR1 signaling pathway. In addition, the FGFR1-Fc fusion protein significantly inhibited angiogenesis in an embryonic chorioallantoic membrane model. The FGFR1-Fc fusion protein may be an effective therapeutic candidate for LSCC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Inmunoglobulina G , Neoplasias Pulmonares , Proteínas Recombinantes de Fusión , Humanos , Factor 2 de Crecimiento de Fibroblastos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Proliferación Celular , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Pulmón/metabolismo , Línea Celular Tumoral
9.
Adv Sci (Weinh) ; 11(4): e2306289, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38044313

RESUMEN

Rapid and effective control of non-compressible massive hemorrhage poses a great challenge in first-aid and clinical settings. Herein, a biopolymer-based powder is developed for the control of non-compressible hemorrhage. The powder is designed to facilitate rapid hemostasis by its excellent hydrophilicity, great specific surface area, and adaptability to the shape of wound, enabling it to rapidly absorb fluid from the wound. Specifically, the powder can undergo sequential cross-linking based on "click" chemistry and Schiff base reaction upon contact with the blood, leading to rapid self-gelling. It also exhibits robust tissue adhesion through covalent/non-covalent interactions with the tissues (adhesive strength: 89.57 ± 6.62 KPa, which is 3.75 times that of fibrin glue). Collectively, this material leverages the fortes of powder and hydrogel. Experiments with animal models for severe bleeding have shown that it can reduce the blood loss by 48.9%. Studies on the hemostatic mechanism also revealed that, apart from its physical sealing effect, the powder can enhance blood cell adhesion, capture fibrinogen, and synergistically induce the formation of fibrin networks. Taken together, this hemostatic powder has the advantages for convenient preparation, sprayable use, and reliable hemostatic effect, conferring it with a great potential for the control of non-compressible hemorrhage.


Asunto(s)
Coagulantes , Hemostáticos , Animales , Polvos , Adherencias Tisulares , Hemorragia , Hemostáticos/farmacología
10.
Transl Res ; 266: 49-56, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37989391

RESUMEN

BACKGROUND: Patients with birth defects (BD) exhibit an elevated risk of cancer. We aimed to investigate the potential link between pediatric cancers and BDs, exploring the hypothesis of shared genetic defects contributing to the coexistence of these conditions. METHODS: This study included 1454 probands with BDs (704 females and 750 males), including 619 (42.3%) with and 845 (57.7%) without co-occurrence of pediatric onset cancers. Whole genome sequencing (WGS) was done at 30X coverage through the Kids First/Gabriella Miller X01 Program. RESULTS: 8211 CNV loci were called from the 1454 unrelated individuals. 191 CNV loci classified as pathogenic/likely pathogenic (P/LP) were identified in 309 (21.3%) patients, with 124 (40.1%) of these patients having pediatric onset cancers. The most common group of CNVs are pathogenic deletions covering the region ChrX:52,863,011-55,652,521, seen in 162 patients including 17 males. Large recurrent P/LP duplications >5MB were detected in 33 patients. CONCLUSIONS: This study revealed that P/LP CNVs were common in a large cohort of BD patients with high rate of pediatric cancers. We present a comprehensive spectrum of P/LP CNVs in patients with BDs and various cancers. Notably, deletions involving E2F target genes and genes implicated in mitotic spindle assembly and G2/M checkpoint were identified, potentially disrupting cell-cycle progression and providing mechanistic insights into the concurrent occurrence of BDs and cancers.


Asunto(s)
Variaciones en el Número de Copia de ADN , Neoplasias , Masculino , Niño , Femenino , Humanos , Variaciones en el Número de Copia de ADN/genética , Secuenciación Completa del Genoma , Neoplasias/epidemiología , Neoplasias/genética , Comorbilidad
11.
Mater Today Bio ; 23: 100835, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37928253

RESUMEN

Bone regeneration following trauma, tumor resection, infection, or congenital disease is challenging. Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia. It can result in complications affecting multiple systems including the musculoskeletal system. The increased number of diabetes-related fractures poses a great challenge to clinical specialties, particularly orthopedics and dentistry. Various pathological factors underlying DM may directly impair the process of bone regeneration, leading to delayed or even non-union of fractures. This review summarizes the mechanisms by which DM hampers bone regeneration, including immune abnormalities, inflammation, reactive oxygen species (ROS) accumulation, vascular system damage, insulin/insulin-like growth factor (IGF) deficiency, hyperglycemia, and the production of advanced glycation end products (AGEs). Based on published data, it also summarizes bone repair strategies in diabetic conditions, which include immune regulation, inhibition of inflammation, reduction of oxidative stress, promotion of angiogenesis, restoration of stem cell mobilization, and promotion of osteogenic differentiation, in addition to the challenges and future prospects of such approaches.

12.
Biochem Biophys Res Commun ; 689: 149238, 2023 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-37979329

RESUMEN

UBE2T is an E2 ubiquitin ligase critical for ubiquitination of substrate and plays important roles in many diseases. Despite the important function, UBE2T is considered as an undruggable target due to lack of a pocket for binding to small molecules with satisfied properties for clinical applications. To develop potent and specific UBE2T inhibitors, we adopted a high-throughput screening assay and two compounds-ETC-6152 and ETC-9004 containing a sulfone tetrazole scaffold were identified. Solution NMR study demonstrated the direct interactions between UBE2T and compounds in solution. Further co-crystal structures reveal the binding modes of these compounds. Both compound hydrolysation and formation of a hydrogen bond with the thiol group of the catalytic cysteine were observed. The formation of covalent complex was confirmed with mass spectrometry. As these two compounds inhibit ubiquitin transfer, our study provides a strategy to develop potent inhibitors of UBE2T.


Asunto(s)
Cisteína , Ubiquitina , Ubiquitina/metabolismo , Cisteína/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismo , Ubiquitinación , Ensayos Analíticos de Alto Rendimiento
13.
Orthop Surg ; 15(11): 2766-2776, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37688429

RESUMEN

The optimal surgical intervention for lateral patellar instability remains a topic of controversy despite satisfactory clinical outcomes and low re-dislocation rates reported in numerous studies following medial patellofemoral ligament reconstruction (MPFLR) with and without tibial tubercle transfer (TTT). The purpose of this systematic review and meta-analysis is to investigate the hypothesis that combining MPFLR with TTT provides reduced complication rates and improved clinical outcomes to isolated MPFLR in patients with lateral patellar instability. We conducted a comprehensive systematic review and meta-analysis of comparative trials involving MPFLR with and without TTT, sourcing data from PubMed, the Cochrane Library, Embase, and Web of Science. The primary clinical outcomes analyzed included the Kujala score, the Lysholm score, complication rates, and the Caton-Deschamps index (CDI). Random or fixed effects were used for the meta-analysis. Postoperatively, there were no significant differences observed in the Kujala and Lysholm scores between MPFLR and MPFLR + TTT (p = 0.053). At the final follow-up, the CDI had decreased 0.015 (95% CI -0.044, 0.013; p = 0.289) points in the MPFLR group, with no statistical significance. In contrast, the MPFLR + TTT group demonstrated a significant decrease of 0.207 (95% CI -0.240, -0.174; p = 0.000) points in CDI. Notably, the complication rate was higher in the MPFLR + TTT group compared to the MPFLR-only group (RR = 2.472; 95% CI 1.638, 3.731; p = 0.000). Both MPFLR and MPFLR + TTT procedures yield significant improvements in the Kujala and Lysholm scores. However, the MPFLR + TTT approach results in an apparent improvement in CDI and corrects patellar maltracking, particularly in cases involving high tibial tuberosity-trochlear groove (TT-TG) (>20 mm) or patella alta (CDI > 1.2), while MPFLR alone cannot. It is essential to consider the higher complication rate of MPFLR + TTT, which suggests that MPFLR alone may be sufficient for patients without high TT-TG or patella alta.


Asunto(s)
Inestabilidad de la Articulación , Luxación de la Rótula , Articulación Patelofemoral , Humanos , Inestabilidad de la Articulación/cirugía , Inestabilidad de la Articulación/etiología , Luxación de la Rótula/cirugía , Articulación Patelofemoral/cirugía , Articulación de la Rodilla/cirugía , Ligamentos Articulares/cirugía , Tibia/cirugía , Rótula/cirugía , Estudios Retrospectivos
14.
BMC Pulm Med ; 23(1): 336, 2023 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-37689634

RESUMEN

BACKGROUND: Endobronchial ultrasonography-guided transbronchial needle aspiration biopsy (EBUS-TBNA) has been used for more than 10 years in China. Its clinical application and diagnostic value in different diseases with large sample was lack of report. METHODS: A retrospective analysis was performed about the application and diagnostic value of EBUS-TBNA in different disease of patients in Respiratory Intervention Center of Guangzhou Institute of Respiratory Health from January 2012 to July 2020. RESULTS: A total 5758 patients were included with 182 patients excluded for lack of information. Finally, data of 5576 patients (3798 males and 1778 females) were analyzed. For anesthetize, most patients were undergoing general anesthesia of intravenous with spontaneous breathing (69.4%), followed by general anesthesia of intravenous and inhalation with tracheal intubation and mechanical ventilation (17.9%) and conscious sedation and analgesia (12.8%). Lymph nodes were the main sites of biopsy obtained (76.4%). Tumors accounted for the highest proportion of disease (66.4%), followed by infection diseases (9.9%), sarcoidosis (3.9%), lymphoma (1.1%), and others (18.7%). The sensitivity of EBUS-TBNA for diagnosis of tumor was 89.7%, and 40.8% for infection diseases. There were significant differences in the puncture site and proportions of diseases between male and females (both p < 0.05). Higher diagnostic value was found in male patients (p < 0.05). CONCLUSION: EBUS-TBNA has good diagnostic value for different mediastinal and central pulmonary space-occupying lesions diseases, with highest sensitivity for tumors. Higher diagnostic value was found in male patients.


Asunto(s)
Analgesia , Femenino , Humanos , Masculino , Estudios Retrospectivos , Administración Intravenosa , Anestesia General , Biopsia con Aguja
15.
J Community Genet ; 14(6): 505-517, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37700208

RESUMEN

Circassians and Chechens in Jordan, both with Caucasian ancestry, are genetically isolated due to high rate of endogamous marriages. Recent interest in these populations has led to studies on their genetic similarities, differences, and epidemiological differences in various diseases. Research has explored their predisposition to conditions like diabetes, hypertension, and cancer. Moreover, pharmacogenetic (PGx) studies have also investigated medication response variations within these populations, and forensic studies have further contributed to understanding these populations. In this review article, we first discuss the background of these minority groups. We then show the results of a principle component analysis (PCA) to investigate the genetic relationships between Circassian and Chechen populations living in Jordan. We here present a summary of the findings from the 10 years of research conducted on them. The review article provides a comprehensive summary of research findings that are truly valuable for understanding the unique genetic characteristics, diseases' prevalence, and medication responses among Circassians and Chechens living in Jordan. We believe that gaining deeper comprehension of the root causes of various diseases and developing effective treatment methods that benefit the society as a whole are imperative to engaging a wide range of ethnic groups in genetic research.

16.
Stem Cell Res Ther ; 14(1): 273, 2023 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-37759328

RESUMEN

BACKGROUND: Identification of promising targeted antigens that exhibited cancer-specific expression is a crucial step in the development of novel antibody-targeted therapies. We here aimed to investigate the anti-tumor activity of a novel monoclonal antibody (mAb) 11C9 and identify the antibody tractable target in the hepatocellular cancer stem cells (HCSCs). METHODS: The identification of the targeted antigen was conducted using SDS-PAGE, western blot, mass spectrometry, and co-immunoprecipitation. Silence of HSP90 was induced by siRNA interference. Positive cells were sorted by fluorescence-activated cell sorting. Double-immunofluorescent (IF) staining and two-color flow cytometry detected the co-expression. Self-renewal, invasion, and drug resistance were assessed by sphere formation, matrigel-coated Transwell assay, and CCK-8 assay, respectively. Tumorigenicity was evaluated in mouse xenograft models. RNA-seq and bioinformatics analysis were performed to explore the mechanism of mAb 11C9 and potential targets. RESULTS: MAb 11C9 inhibited invasion and self-renewal abilities of HCC cell lines and reversed the cisplatin resistance. HSP90 (~ 95 kDa) was identified as a targeted antigen of mAb 11C9. Tissue microarrays and online databases revealed that HSP90 was overexpressed in HCC and associated with a poor prognosis. FACS and double-IF staining showed the co-expression of HSP90 and CSCs markers (CD90 and ESA). In vitro and in vivo demonstrated the tumorigenic potentials of HSP90. The inhibition of HSP90 by siRNA interference or 17-AAG inhibitor both decreased the number of invasion, sphere cells, and CD90+ or ESA+ cells, as well as reversed the resistance. Bioinformatics analysis and western blot verified that HSP90 activated Wnt/ß-catenin signaling. CONCLUSIONS: The study preliminarily revealed the anti-tumor activity of mAb 11C9. More importantly, we identified HSP90 as a targeted antigen of mAb 11C9, which functions as an oncogene in phenotype shaping, stemness maintenance, and therapeutic resistance by activating Wnt/ß-catenin signaling.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratones , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , beta Catenina/metabolismo , Línea Celular Tumoral , ARN Interferente Pequeño/metabolismo , Modelos Animales de Enfermedad , Células Madre Neoplásicas/metabolismo , Proliferación Celular
17.
Mol Cancer ; 22(1): 126, 2023 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-37543594

RESUMEN

Children with birth defects (BD) express distinct clinical features that often have various medical consequences, one of which is predisposition to the development of cancers. Identification of the underlying genetic mechanisms related to the development of cancer in BD patients would allow for preventive measures. We performed a whole genome sequencing (WGS) study on blood-derived DNA samples from 1566 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumors, 767 cancer-free BD probands, and 345 healthy individuals. Exclusive recurrent variants were identified in BD-cancer and BD-only patients and mapped to their corresponding genomic regions. We observed statistically significant overlaps for protein-coding/ncRNA with exclusive variants in exons, introns, ncRNAs, and 3'UTR regions. Exclusive exonic variants, especially synonymous variants, tend to occur in prior exons locus in BD-cancer children. Intronic variants close to splicing site (< 500 bp from exon) have little overlaps in BD-cancer and BD-only patients. Exonic variants in non-coding RNA (ncRNA) tend to occur in different ncRNAs exons regardless of the overlaps. Notably, genes with 5' UTR variants are almost mutually exclusive between the two phenotypes. In conclusion, we conducted the first genomic study to explore the impact of recurrent variants exclusive to the two distinguished clinical phenotypes under study, BD with or without cancer, demonstrating enrichment of selective protein-coding/ncRNAs differentially expressed between these two phenotypes, suggesting that selective genetic factors may underlie the molecular processes of pediatric cancer development in BD children.


Asunto(s)
Neoplasias , Empalme del ARN , Humanos , Mutación , Exones , Genómica , Neoplasias/genética , Intrones
19.
ACS Chem Neurosci ; 14(17): 3113-3124, 2023 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-37559405

RESUMEN

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has been confirmed to contribute to brain injury in ischemic stroke via promoting excitotoxicity and necroptosis. Telaprevir, a hepatitis C virus protease inhibitor, is predicted to be a potential MALT1 inhibitor. Here, we showed that telaprevir protected against cerebral ischemic injury via inhibiting MALT1, thereby preventing glutamate receptor ionotropic NMDA 2B (GluN2B) activation, limiting calcium overload, and suppressing necroptosis. In ischemic stroke mice, telaprevir reduced infarct volume, improved the long-term survival rate, and enhanced sensorimotor, memory, and cognitive functions. In hypoxia-treated nerve cells, telaprevir decreased the intracellular calcium concentrations and reduced LDH release. Mechanistically, telaprevir inhibited MALT1 protease activity, thus decreasing the membrane protein level of GluN2B and its phosphorylation through reducing the level of STEP61. Moreover, telaprevir was able to inhibit the levels of necroptosis-associated proteins. According to these results, it can be concluded that telaprevir alleviates neuronal brain injury in stroke mice via restraining GluN2B activation and suppresses the receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway through inhibiting MALT1. Thus, telaprevir might have a novel indication for treating patients with ischemic stroke.


Asunto(s)
Lesiones Encefálicas , Accidente Cerebrovascular Isquémico , Ratones , Animales , Calcio , Proteínas Quinasas/metabolismo , Necroptosis , Cognición
20.
Healthcare (Basel) ; 11(14)2023 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-37510421

RESUMEN

The prevalence of vaping worldwide is showing an upward trend. This study aimed to determine the factors associated with motivation to quit vaping among vapers in the Federal Territory of Kuala Lumpur, Malaysia, through a cross-sectional, purposive sampling study. Respondents were required to complete a questionnaire consisting of vapers' sociodemographic questions, habitual behavioral pattern questions, the e-Fagerström Test of Nicotine Dependence, the Glover-Nilsson Smoking Behavioral Dependence Questionnaire, perception questions, motivation to quit questions, and withdrawal symptom questions. A total of 311 vapers participated in this study. The majority of the vapers were male (84.6%), younger (18-25 years) (55.3%), and with monthly income less than RM 4000 (USD 868; 83.9%). The level of motivation to quit vaping was found to have a significant association with the perception of vaping being as satisfying as cigarette smoking (p = 0.006) and mild to very strong nicotine dependence (p = 0.001). Participants who recorded moderate and strong habitual vaping behaviors had lower odds of having high motivation to quit vaping compared to those recording slight habitual behaviors (OR = 0.279, 95%CI(0.110-0.708), p = 0.007 and OR = 0.185, 95%CI(0.052-0.654), p = 0.009, respectively). Factors associated with higher motivation to quit vaping could be explored to gain better understanding of how to increase their motivation level for future quit attempts.

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