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1.
Afr J Reprod Health ; 28(9): 163-171, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39373239

RESUMO

This study examines the effects of comprehensive nursing care on hand-foot syndrome (HFS) in breast cancer patients treated with capecitabine. A retrospective analysis was conducted on 71 patients, divided into a study group receiving comprehensive care and a control group receiving conventional care. Results showed that the study group experienced significant improvements in skin symptoms, self-efficacy, quality of life, and lower anxiety and depression levels compared to the control group. Additionally, patients who were compliant with medications were notably better in the study group. Comprehensive care effectively alleviates the symptoms of hand-foot syndrome in breast cancer patients treated with capecitabine and enhances patient well-being.


Cette étude examine les effets des soins infirmiers complets sur le syndrome main-pied (SMP) chez les patientes atteintes de cancer du sein traitées par capécitabine. Une analyse rétrospective a été réalisée sur 71 patientes, divisées en un groupe d'étude recevant des soins complets et un groupe témoin recevant des soins conventionnels. Les résultats ont montré que le groupe d'étude a connu des améliorations significatives des symptômes cutanés, de l'auto-efficacité, de la qualité de vie, ainsi qu'une réduction des niveaux d'anxiété et de dépression par rapport au groupe témoin. De plus, les patientes adhérant au traitement médicamenteux étaient notablement meilleures dans le groupe d'étude. Les soins complets atténuent efficacement les symptômes du syndrome main-pied chez les patientes atteintes de cancer du sein traitées par capécitabine et améliorent leur bien-être.


Assuntos
Antimetabólitos Antineoplásicos , Neoplasias da Mama , Capecitabina , Síndrome Mão-Pé , Qualidade de Vida , Humanos , Capecitabina/efeitos adversos , Capecitabina/uso terapêutico , Síndrome Mão-Pé/etiologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Adulto , Resultado do Tratamento
2.
Semin Cancer Biol ; 2024 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-39442678

RESUMO

Immunotherapy has revolutionized the management of various types of cancers, even those previously deemed untreatable. Nonetheless, these medications have been associated with inflammation and damage across various organs. These challenges are exemplified by the adverse cardiovascular impacts of cancer immunotherapy, which need comprehensive understanding, clarification, and management integrated into the overall care of cancer patients. Numerous anticancer immunotherapies have been linked to the prevalence and severity of cardiovascular toxicity. These challenges emphasize the importance of conducting fundamental and applied research to elucidate disease causes, discover prognostic indicators, enhance diagnostic methods, and create successful therapies. Despite the acknowledged importance of T cells, there remains a knowledge gap regarding the inciting antigens, the reasons for their recognition, and the mechanisms of how they contribute to cardiac cell injury. In this review, we summarize the molecular mechanism, epidemiology, diagnosis, pathophysiology and corresponding treatment of cardiovascular toxicity induced by immunotherapy, including immune checkpoint inhibitors (ICIs), adoptive cell therapies (ACT), and bi-specific T-cell engagers (BiTEs) among others. By elucidating these aspects, we aim to provide a better understanding of immunotherapies in cancer treatment and offer guidance for their clinical application.

3.
J Med Chem ; 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39311434

RESUMO

STAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with Ki = 3.5 µM binding affinity, we obtained AK-068 with Ki = 6 nM to STAT6 and at least >85-fold binding selectivity over STAT5. Using AK-068 and cereblon ligands, we discovered AK-1690 as the first, potent and selective PROTAC STAT6 degrader. AK-1690 effectively induces degradation of STAT6 protein in cells with DC50 values of as low as 1 nM while showing minimal effect on other STAT members up to 10 µM. A single dose of AK-1690 effectively depletes STAT6 in mouse tissues. Determination of the first cocrystal structure of STAT6 in complex with AK-1690 provides a structural basis for their interactions. AK-1690 is a powerful tool with which to investigate the roles of STAT6 in human diseases and biological processes and a promising lead compound for further optimization.

4.
J Med Chem ; 67(16): 14125-14154, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39132814

RESUMO

The bromodomain-containing protein BRD9 has emerged as an attractive therapeutic target. In the present study, we successfully identified a number of highly potent BRD9 degraders by using two different cereblon ligands developed in our laboratory. Further optimization led to the discovery of CW-3308 as a potent, selective, and orally bioavailable BRD9 degrader. It displayed degradation potency (DC50) < 10 nM and efficiency (Dmax) > 90% against BRD9 in the G401 rhabdoid tumor and HS-SY-II synovial sarcoma cell lines and had a high degradation selectivity over BRD7 and BRD4 proteins. CW-3308 achieved 91% of oral bioavailability in mice. A single oral dose efficiently reduced the BRD9 protein by >90% in the synovial sarcoma HS-SY-II xenograft tumor tissue. Oral administration effectively inhibited HS-SY-II xenograft tumor growth in mice. CW-3308 is a promising lead compound for further optimization and extensive evaluation for the treatment of synovial sarcoma, rhabdoid tumor, and other BRD9-dependent human diseases.


Assuntos
Fatores de Transcrição , Humanos , Animais , Administração Oral , Camundongos , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto , Proteólise/efeitos dos fármacos , Descoberta de Drogas , Camundongos Nus , Disponibilidade Biológica , Proteínas que Contêm Bromodomínio
5.
Artigo em Inglês | MEDLINE | ID: mdl-38972436

RESUMO

BACKGROUND: There are limited clinical data regarding the additional yields of random biopsies (RBs) during colorectal cancer surveillance in patients with inflammatory bowel disease. To assess the additional yield of RB, a systematic review and meta-analysis was conducted. METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched for studies investigating the preferred colonoscopy surveillance approach for inflammatory bowel disease patients. The additional yield, detection rate, procedure time, and withdrawal time were pooled. RESULTS: Thirty-seven studies (48 arms) were included in the meta-analysis with 9051 patients. The additional yields of RB were 10.34% in per-patient analysis and 16.20% in per-lesion analysis. The detection rates were 1.31% and 2.82% in per-patient and per-lesion analysis, respectively. Subgroup analysis showed a decline in additional yields from 14.43% to 0.42% in the per-patient analysis and from 19.20% to 5.32% in the per-lesion analysis for studies initiated before and after 2011. In per-patient analysis, the additional yields were 4.83%, 10.29%, and 56.05% for primary sclerosing cholangitis (PSC) proportions of 0% to 10%, 10% to 30%, and 100%, respectively. The corresponding detection rates were 0.56%, 1.40%, and 19.45%. In the per-lesion analysis, additional yields were 11.23%, 21.06%, and 45.22% for PSC proportions of 0% to 10%, 10% to 30%, and 100%, respectively. The corresponding detection rates were 2.09%, 3.58%, and 16.24%. CONCLUSIONS: The additional yields of RB were 10.34% and 16.20% for per-patient and per-lesion analyses, respectively. Considering the decreased additional yields in studies initiated after 2011, and the influence of PSC, endoscopy centers lacking full high-definition equipment should consider incorporating RB in the standard colonoscopy surveillance for inflammatory bowel disease patients, especially in those with PSC.

6.
Biomater Adv ; 163: 213965, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39053386

RESUMO

The unique amino acid composition of elastin peptide (EP) makes it an excellent resource to obtain antioxidant peptides. It exhibits high elastase inhibitory activity with the potential to resist skin aging and is currently used in a many cosmetic products. However, the inherent low permeability of the skin limits its ability to penetrate the skin. To address this issue, a deep eutectic solvent (SAB) with excellent bioactivity was synthesized from betaine and succinic acid and used as a permeation enhancer to improve the absorption and utilization of EP in this paper. The results showed that low SAB concentrations significantly increased the transdermal delivery of EP. The 3D epidermal skin model (EpiKutis®) demonstrated that SAB/EP induced the synthesis of hyaluronic acid (HA) and filaggrin (FLG), accelerated skin barrier repair, and reduced water loss. Additionally, the zebrafish embryonic model showed that SAB/EP could reduce melanin secretion, decrease melanin deposition, and have an ameliorative effect on skin photoaging. Cellular experiments proved that SAB/EP can stimulate human skin fibroblasts to secrete procollagen I and elastin, improving skin elasticity and anti-wrinkle. The combination of EP and DES is a new attempt that is expected to be used as a safe and effective anti-wrinkle cosmetic material.


Assuntos
Administração Cutânea , Betaína , Elastina , Proteínas Filagrinas , Envelhecimento da Pele , Pele , Elastina/metabolismo , Envelhecimento da Pele/efeitos dos fármacos , Humanos , Animais , Betaína/farmacologia , Betaína/administração & dosagem , Betaína/química , Betaína/análogos & derivados , Pele/metabolismo , Pele/efeitos dos fármacos , Peixe-Zebra , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Peptídeos/química
7.
J Affect Disord ; 362: 853-858, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39029675

RESUMO

BACKGROUND: Antenatal depression may result in adverse outcomes for both the mother and the offspring. However, few studies have focused on the screening of pregnant women at a higher risk for antenatal depression in the first trimester. The present study aimed to assess the effect of lifestyle and family relationships on antenatal depression in the first trimester in a large Chinese population. METHODS: Cross-sectional population data were obtained from a real-world cross-sectional survey conducted in Shenzhen, China from 2020 to 2024. The data on sociodemographic characteristics, lifestyle, and family relationships were obtained using self-reported questionnaires. Antenatal depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS), with a score of ≥13 indicating the presence of probable antenatal depression. A binary logistic regression model was used to identify the risk factors of antenatal depression. RESULTS: A total of 42,363 pregnant women in the first trimester were recruited in the cross-sectional survey, among whom 3107 (7.3 %) had probable antenatal depression. We found (1) age < 25 years, (2) low or moderate economic status, (3) smoking, (4) partner smoking, (5) alcohol use, (6) lack of physical exercise, (7) poor or moderate living environment, (8) low or moderate marital happiness, and (9) never talking about problems were associated with antenatal depression. However, level of education, employment status, partner alcohol use, and living alone were not significantly related to antenatal depression in the first trimester. LIMITATIONS: The cross-sectional design and the use of self-report measures must be considered while interpreting the results. CONCLUSIONS: This study suggested that the prevalence of antenatal depression in the first trimester was 7.3 %. Public health prevention efforts aimed at reducing the prevalence of antenatal depression are recommended. Early identification of women at a higher risk in early pregnancy is necessary for preventing antenatal depression and improving quality of life.


Assuntos
Complicações na Gravidez , Primeiro Trimestre da Gravidez , Humanos , Feminino , Gravidez , China/epidemiologia , Estudos Transversais , Adulto , Fatores de Risco , Prevalência , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/psicologia , Depressão/epidemiologia , Adulto Jovem , Estilo de Vida
8.
Medicine (Baltimore) ; 103(24): e38468, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38875434

RESUMO

INTRODUCTION: Laparoscopic hepatectomy (LH) poses a high risk of carbon dioxide embolism due to extensive hepatic transection, long surgery duration, and dissection of the large hepatic veins or vena cava. PATIENT CONCERNS: A 65-year-old man was scheduled to undergo LH. Following intraperitoneal carbon dioxide (CO2) insufflation and hepatic portal occlusion, the patient developed severe hemodynamic collapse accompanied by a decrease in the pulse oxygen saturation (SpO2). DIAGNOSIS: Although a decrease in end-tidal carbon dioxide (ETCO2) was not observed, CO2 embolism was still suspected because of the symptoms. INTERVENTIONS AND OUTCOMES: The patient was successfully resuscitated after the immediate discontinuation of CO2 insufflation and inotrope administration. CO2 embolism must always be suspected during laparoscopic surgery whenever sudden hemodynamic collapse associated with decreased pulse oxygen saturation occurs, regardless of whether ETCO2 changes. Instant arterial blood gas analysis is imperative, and a significant difference between PaCO2 and ETCO2 is indicative of carbon dioxide embolism. CONCLUSION: Instant arterial blood gas analysis is imperative, and a significant difference between PaCO2 and ETCO2 is indicative of carbon dioxide embolism.


Assuntos
Dióxido de Carbono , Embolia Aérea , Hepatectomia , Laparoscopia , Humanos , Masculino , Idoso , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Hepatectomia/efeitos adversos , Hepatectomia/métodos , Embolia Aérea/etiologia , Insuflação/efeitos adversos , Insuflação/métodos , Gasometria/métodos , Complicações Intraoperatórias/etiologia , Complicações Intraoperatórias/diagnóstico
9.
Inflamm Res ; 73(7): 1173-1184, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38739197

RESUMO

OBJECTIVE AND DESIGN: To elucidate Sirt1's role in gouty arthritis inflammation and its potential mechanisms. MATERIAL: Constructed murine models of gouty arthritis and conducted THP-1 cell experiments. TREATMENT: 1 mg of MSU crystals injected into mice ankle joints for a 72-h intervention. After a 3-h pre-treatment with Sirt1-specific inhibitor (EX527) and agonist (SRT2104), inflammation was induced for 21 h using lipopolysaccharide (LPS) plus MSU crystals. METHODS: We assessed gouty arthritis severity through joint inflammation index, swelling, and hematoxylin and eosin (H&E) staining, and measured CD68 mononuclear macrophages and Sirt1 expression in synovial tissue via immunohistochemistry. ELISA, NO assay, RT-qPCR, Flow cytometry, and Western blot were utilized to examine macrophage inflammatory factors, polarization, reactive oxygen species(ROS), MAPK/NF-κB/AP-1 and Nrf2/HO-1 pathways proteins. RESULTS: Significant joint swelling, synovial tissue edema, and inflammatory cell infiltration were observed. CD68 mononuclear macrophages and Sirt1 expression were elevated in synovium. Sirt1 activation decreased inflammatory factors, M1 polarization, and ROS generation. Sirt1 activation reduced p38/JNK phosphorylation, thereby inhibiting downstream NF-κB p65/AP-1 and enhancing Nrf2/HO-1, thus suppressing inflammation. CONCLUSIONS: Sirt1 alleviates M1 macrophage polarization and inflammation in gouty arthritis by inhibiting the MAPK/NF-κB/AP-1 pathway and activating the Nrf2/HO-1 pathway. Thus, activating Sirt1 may provide a new therapeutic target for gouty arthritis.


Assuntos
Artrite Gotosa , Heme Oxigenase-1 , Macrófagos , Fator 2 Relacionado a NF-E2 , NF-kappa B , Sirtuína 1 , Fator de Transcrição AP-1 , Animais , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Artrite Gotosa/imunologia , Sirtuína 1/metabolismo , Sirtuína 1/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Humanos , Masculino , NF-kappa B/metabolismo , Heme Oxigenase-1/metabolismo , Camundongos , Fator de Transcrição AP-1/metabolismo , Células THP-1 , Camundongos Endogâmicos C57BL , Inflamação , Transdução de Sinais/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Carbazóis , Proteínas de Membrana
10.
Molecules ; 29(10)2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38792026

RESUMO

Ethanamizuril (EZL) is a new anticoccidial drug developed by our Shanghai Veterinary Research Institute. Since EZL is almost insoluble in water, we conducted a study to improve the solubility of EZL by forming inclusion complexes with ß-cyclodextrin (ß-CD) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD). In this study, we performed molecular docking and then systematically compared the interactions of EZL with ß-CD and HP-ß-CD in both aqueous solution and the solid state, aiming to elucidate the solubilization effect and mechanism of cyclodextrins (CDs). The interactions were also examined in the solid state using DSC, PXRD, and FT-IR. The interactions of EZL with CDs in an aqueous solution were investigated using PSA, UV-vis spectroscopy, MS, 1H NMR, and 2D ROESY. The results of phase solubility experiments revealed that both ß-CD and HP-ß-CD formed inclusion complexes with EZL in a 1:1 molar ratio. Among them, HP-ß-CD exhibited higher Kf (stability constant) and CE (complexation efficiency) values as well as a stronger solubilization effect. Furthermore, the two cyclodextrins were found to interact with EZL in a similar manner. The results of our FT-IR and 2D ROESY experiments are in agreement with the theoretical results derived from molecular simulations. These results indicated that intermolecular hydrogen bonds existing between the C=O group on the triazine ring of EZL and the O-H group of CDs, as well as the hydrophobic interactions between the hydrogen on the benzene ring of EZL and the hydrogen of CDs, played crucial roles in the formation of EZL/CD inclusion complexes. The results of this study can lay the foundation for the future development of high-concentration drinking water delivery formulations for EZL.

11.
Materials (Basel) ; 17(3)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38591509

RESUMO

In this paper, the damage monitoring investigation based on the remote bonding fiber Bragg grating sensing is performed on the aerospace aluminum alloy thin-walled structure with prefabricated damage. Firstly, an ultrasonic excitation-fiber Bragg gratings (UE-FBGs) sensing experimental platform is established for the simulation of defects monitoring, in which the sensors are placed at a certain distance from the bonding area. Secondly, different arrangements of exciters and receivers are utilized for the original signals and the damage signals. Subsequently, the raw signals are processed by filter and feature extraction in order to denoise the signals and acquire the parameters sensitive to the damage. Finally, an improved Reconstruction for Image Defects (RAPID) algorithm is used to locate and reconstruct the pre-existing damage. The results show that the proposed system improves the sensitivity of the FBG receiver signal and the accuracy of the damage imaging.

12.
BMC Med Imaging ; 24(1): 77, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38566000

RESUMO

BACKGROUND: To investigate the value of a nomogram model based on the combination of clinical-CT features and multiphasic enhanced CT radiomics for the preoperative prediction of the microsatellite instability (MSI) status in colorectal cancer (CRC) patients. METHODS: A total of 347 patients with a pathological diagnosis of colorectal adenocarcinoma, including 276 microsatellite stabilized (MSS) patients and 71 MSI patients (243 training and 104 testing), were included. Univariate and multivariate regression analyses were used to identify the clinical-CT features of CRC patients linked with MSI status to build a clinical model. Radiomics features were extracted from arterial phase (AP), venous phase (VP), and delayed phase (DP) CT images. Different radiomics models for the single phase and multiphase (three-phase combination) were developed to determine the optimal phase. A nomogram model that combines clinical-CT features and the optimal phasic radscore was also created. RESULTS: Platelet (PLT), systemic immune inflammation index (SII), tumour location, enhancement pattern, and AP contrast ratio (ACR) were independent predictors of MSI status in CRC patients. Among the AP, VP, DP, and three-phase combination models, the three-phase combination model was selected as the best radiomics model. The best MSI prediction efficacy was demonstrated by the nomogram model built from the combination of clinical-CT features and the three-phase combination model, with AUCs of 0.894 and 0.839 in the training and testing datasets, respectively. CONCLUSION: The nomogram model based on the combination of clinical-CT features and three-phase combination radiomics features can be used as an auxiliary tool for the preoperative prediction of the MSI status in CRC patients.


Assuntos
Neoplasias Colorretais , Nomogramas , Humanos , Instabilidade de Microssatélites , Radiômica , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia
13.
ACS Appl Mater Interfaces ; 16(15): 18252-18267, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38581365

RESUMO

Nitric oxide (NO) intervenes, that is, a potential treatment strategy, and has attracted wide attention in the field of tumor therapy. However, the therapeutic effect of NO is still poor, due to its short half-life and instability. Therapeutic concentration ranges of NO should be delivered to the target tissue sites, cell, and even subcellular organelles and to control NO generation. Mitochondria have been considered a major target in cancer therapy for their essential roles in cancer cell metabolism and apoptosis. In this study, mesoporous silicon-coated gold nanorods encapsulated with a mitochondria targeted and the thermosensitive lipid layer (AuNR@MSN-lipid-DOX) served as the carrier to load NO prodrug (BNN6) to build the near-infrared-triggered synergetic photothermal NO-chemotherapy platform (AuNR@MSN(BNN6)-lipid-DOX). The core of AuNR@MSN exhibited excellent photothermal conversion capability and high loading efficiency in terms of BNN6, reaching a high value of 220 mg/g (w/w), which achieved near-infrared-triggered precise release of NO. The outer biocompatible lipid layer, comprising thermosensitive phospholipid DPPC and mitochondrial-targeted DSPE-PEG2000-DOX, guided the whole nanoparticle to the mitochondria of 4T1 cells observed through confocal microscopy. In the mitochondria, the nanoparticles increased the local temperature over 42 °C under NIR irradiation, and a high NO concentration from BNN6 detected by the NO probe and DSPE-PEG2000-DOX significantly inhibited 4T1 cancer cells in vitro and in vivo under the synergetic photothermal therapy (PTT)-NO therapy-chemotherapy modes. The built NIR-triggered combination therapy nanoplatform can serve as a strategy for multimodal collaboration.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Fosfatidiletanolaminas , Polietilenoglicóis , Doxorrubicina/farmacologia , Óxido Nítrico , Fototerapia , Nanopartículas/uso terapêutico , Mitocôndrias , Lipídeos , Linhagem Celular Tumoral
14.
bioRxiv ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38586029

RESUMO

Prostate cancer is an exemplar of an enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised of chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. The paralog lysine acetyltransferases p300 and CBP deposit histone marks that are associated with enhancer activation. Here, we demonstrate that p300/CBP are determinant cofactors of the active AR enhanceosome in prostate cancer. Histone H2B N-terminus multisite lysine acetylation (H2BNTac), which is exclusively reliant on p300/CBP catalytic function, marked active enhancers and was notably elevated in prostate cancer lesions relative to the adjacent benign epithelia. Degradation of p300/CBP rapidly depleted acetylation marks associated with the active AR enhanceosome, which was only partially phenocopied by inhibition of their reader bromodomains. Notably, H2BNTac was effectively abrogated only upon p300/CBP degradation, which led to a stronger suppression of p300/CBP-dependent oncogenic gene programs relative to bromodomain inhibition or the inhibition of its catalytic domain. In vivo experiments using an orally active p300/CBP proteolysis targeting chimera (PROTAC) degrader (CBPD-409) showed that p300/CBP degradation potently inhibited tumor growth in preclinical models of castration-resistant prostate cancer and synergized with AR antagonists. While mouse p300/CBP orthologs were effectively degraded in host tissues, prolonged treatment with the PROTAC degrader was well tolerated with no significant signs of toxicity. Taken together, our study highlights the pivotal role of p300/CBP in maintaining the active AR enhanceosome and demonstrates how target degradation may have functionally distinct effects relative to target inhibition, thus supporting the development of p300/CBP degraders for the treatment of advanced prostate cancer.

15.
FASEB J ; 38(6): e23573, 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38526846

RESUMO

Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.


Assuntos
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Camundongos , Animais , RNA Guia de Sistemas CRISPR-Cas , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Mutação , Hipercolesterolemia/genética , Colesterol , Receptores de LDL/genética , Receptores de LDL/metabolismo
16.
J Med Chem ; 67(7): 5275-5304, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38477974

RESUMO

CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC50 ≤ 0.03 nM and Dmax > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3-3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Camundongos , Ratos , Animais , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Proteínas , Proliferação de Células
17.
J Med Chem ; 67(7): 5351-5372, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38530938

RESUMO

CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and are promising cancer therapeutic targets. Herein, we report the discovery of highly potent, selective, and orally bioavailable CBP/p300 degraders using the PROTAC technology with CBPD-409 being the most promising compound. CBPD-409 induces robust CBP/p300 degradation with DC50 0.2-0.4 nM and displays strong antiproliferative effects with IC50 1.2-2.0 nM in the VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. It has a favorable pharmacokinetic profile and achieves 50% of oral bioavailability in mice. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue. CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Animais , Camundongos , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Linhagem Celular Tumoral
18.
Jpn J Radiol ; 42(6): 612-621, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38381249

RESUMO

PURPOSE: To investigate the value of preoperative diagnosis of colorectal adenocarcinoma (CRAC) pathological T staging based on dual-layer spectral-detector computed tomography (DLCT) extracellular volume fraction (ECV) of CRAC lesions. METHODS: We prospectively collected clinical and DLCT imaging data from 165 patients with CRAC who attended two hospitals from June 2022 to April 2023. The enrolled patients were divided into a training group (n = 110, from Hospital 1) and an external validation group (n = 55, from Hospital 2). Measuring and calculating DLCT parameters of lesions, including CT values of 40 and 100 keV virtual mono-energetic images (VMI), iodine concentration (IC) and effective atomic number (Eff-Z) in the arterial phases (AP) and venous phases (VP), and ECV in the delayed phase (DP). The differences in clinical characteristics and DLCT parameters were compared between different pT subgroups. The correlation between DLCT parameters and pT stages were evaluated by Spearman correlation analysis. A multifactorial binary logistic stepwise forward regression analysis was performed to obtain independent influences associated with pT stage. Receiver operating characteristic curves (ROCs) were used to assess diagnostic efficacy and were expressed as area under the curve (AUC). RESULTS: Each DLCT parameter was higher in pT3 stage tumors than in pT1-2 stage tumors (all P < 0.05). The highest correlation was found between ECV and pT stage (r = 0.637). ECV were independent influences associated with pT stage. ECV had excellent diagnostic efficacy for CRAC pT staging in both the training and external validation groups (AUC = 0.919 and 0.892). CONCLUSION: ECV based on DLCT measurement can be used for preoperative noninvasive diagnosis of CRAC pT staging with excellent diagnostic efficacy. It can provide a new imaging marker for the preoperative evaluation of CRAC and help clinicians formulate individualized treatment earlier. However, it needs to be confirmed with a larger sample size.


Assuntos
Adenocarcinoma , Neoplasias Colorretais , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Idoso , Tomografia Computadorizada por Raios X/métodos , Estudos Prospectivos , Adulto , Idoso de 80 Anos ou mais
19.
Am J Chin Med ; 52(1): 1-33, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38351701

RESUMO

Obesity is a common metabolic syndrome that causes a significant burden on individuals and society. Conventional therapies include lifestyle interventions, bariatric surgery, and pharmacological therapies, which are not effective and have a high risk of adverse events. Acupuncture is an effective alternative for obesity, it modulates the hypothalamus, sympathetic activity and parasympathetic activity, obesity-related hormones (leptin, ghrelin, insulin, and CCK), the brain-gut axis, inflammatory status, adipose tissue browning, muscle blood flow, hypoxia, and reactive oxygen species (ROS) to influence metabolism, eating behavior, motivation, cognition, and the reward system. However, hypothalamic regulation by acupuncture should be further demonstrated in human studies using novel techniques, such as functional MRI (fMRI), positron emission tomography (PET), electroencephalogram (EEG), and magnetoencephalography (MEG). Moreover, a longer follow-up phase of clinical trials is required to detect the long-term effects of acupuncture. Also, future studies should investigate the optimal acupuncture therapeutic option for obesity. This review aims to consolidate the recent improvements in the mechanism of acupuncture for obesity as well as discuss the future research prospects and potential of acupuncture for obesity.


Assuntos
Terapia por Acupuntura , Obesidade , Humanos , Obesidade/etiologia , Terapia por Acupuntura/métodos , Tecido Adiposo , Imageamento por Ressonância Magnética/métodos
20.
Heliyon ; 10(1): e23720, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38226247

RESUMO

Background: Acral melanoma (AM), an aggressive subtype of melanoma with poor prognosis, has been increasingly studied. The present study aims to discuss the current status, hotspots and future directions of AM studies through visualized analysis with bibliometrics and knowledge graph. Method: Publications related to acral melanoma from January 1999 to May 2023 were searched and retrieved from the Web of Science. Data extraction and visualization of the top 10 publications by year of publication, journal, country and core author were performed using R Studio (Version 4.3.0) and Scimago Graphica (Version 1.0.34). Co-reference graphs regarding country/region, organization, author, and keywords, as well as reference collaborative network, co-occurrence network, and references were plotted using VOSviewer (Version 1.6.19) and CiteSpace (Version 6.2.R3). Results: A total of 1387 articles related to AM published in English from 1999 to 2023 were included in the present study. A total of 7499 authors were from 2092 organizations in 50 countries. The articles were published in 356 journals, involving 4131 keywords and 28,200 references. The 1387 articles related to AM had been cited a total of 10,014 times by the time of this study. The result showed that Journal of the American Academy of Dermatology had the largest number of citations and citation rate, with a total of 60 publications having been cited 2191 times. Having the top three productivity institutions in the world, the US is the most productive country in this field, with a total of 361 publications. The authors with the highest number of publications were Guo Jun (n = 43) and Si Lu (n = 38) from Peking University. The keyword burstiness test found that "ipilimumab", "open label", "efficacy" and "nivolumab" appeared most frequently in recent years. The co-cited reference timeline graph showed that the clustering of "advanced melanoma" and "melanocytic lesion" has been a hotspot since 2016. Conclusions: The number of AM-related studies has been increasing. The clinical characteristics and immunotherapy of AM are still key research directions, with the US playing a leading role in this field. This bibliometric analysis found up to 1387 publications, which not only comprehensively and quantitatively reflected the research trends and hotspots, but also provided a theoretical basis for future studies of AM. Researchers can benefit from choosing the right journals and finding potential collaborators or partner institutions.

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