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1.
Medicine (Baltimore) ; 103(25): e38543, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38905431

RESUMO

BACKGROUND: Fibrolipoma of the lower lip is an uncommon condition with limited documentation in the literature. This paper provides updated insights into oral and maxillofacial lipomas through a detailed case report and comprehensive literature review, discussing clinical features, pathogenesis, diagnostic approaches, histopathology, and therapeutic strategies. CASE PRESENTATION: A 54-year-old female presented with a painless, enlarging mass on the inner aspect of her right lower lip, first noticed 2 years prior. The mass, now the size of a peanut, interfered with her eating and speech. Physical examination revealed a 2.0 × 2.5 × 1.0 cm mass beneath the mucous membrane of the right lower lip. It was firm, well-demarcated, and mobile. Surgical excision was performed, and histopathological analysis confirmed the diagnosis of a lower lip fibrolipoma. The lesion was successfully removed without recurrence. CONCLUSION: Lipomas in the oral and maxillofacial regions are rare, slow-growing benign tumors, particularly within the lips. Although their diagnosis is straightforward based on clinical presentation, histopathological confirmation is essential. Surgical resection remains the treatment of choice, with excellent prognostic outcomes.


Assuntos
Neoplasias Labiais , Lipoma , Humanos , Feminino , Pessoa de Meia-Idade , Lipoma/diagnóstico , Lipoma/cirurgia , Lipoma/patologia , Neoplasias Labiais/patologia , Neoplasias Labiais/cirurgia , Neoplasias Labiais/diagnóstico , Lábio/patologia , Lábio/cirurgia
2.
J Clin Invest ; 134(13)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722683

RESUMO

This study reports that targeting intrinsically disordered regions of the voltage-gated sodium channel 1.7 (NaV1.7) protein facilitates discovery of sodium channel inhibitory peptide aptamers (NaViPA) for adeno-associated virus-mediated (AAV-mediated), sensory neuron-specific analgesia. A multipronged inhibition of INa1.7, INa1.6, INa1.3, and INa1.1 - but not INa1.5 and INa1.8 - was found for a prototype and named NaViPA1, which was derived from the NaV1.7 intracellular loop 1, and is conserved among the TTXs NaV subtypes. NaViPA1 expression in primary sensory neurons (PSNs) of dorsal root ganglia (DRG) produced significant inhibition of TTXs INa but not TTXr INa. DRG injection of AAV6-encoded NaViPA1 significantly attenuated evoked and spontaneous pain behaviors in both male and female rats with neuropathic pain induced by tibial nerve injury (TNI). Whole-cell current clamp of the PSNs showed that NaViPA1 expression normalized PSN excitability in TNI rats, suggesting that NaViPA1 attenuated pain by reversal of injury-induced neuronal hypersensitivity. IHC revealed efficient NaViPA1 expression restricted in PSNs and their central and peripheral terminals, indicating PSN-restricted AAV biodistribution. Inhibition of sodium channels by NaViPA1 was replicated in the human iPSC-derived sensory neurons. These results summate that NaViPA1 is a promising analgesic lead that, combined with AAV-mediated PSN-specific block of multiple TTXs NaVs, has potential as a peripheral nerve-restricted analgesic therapeutic.


Assuntos
Dependovirus , Canal de Sódio Disparado por Voltagem NAV1.7 , Células Receptoras Sensoriais , Animais , Ratos , Dependovirus/genética , Células Receptoras Sensoriais/metabolismo , Masculino , Humanos , Feminino , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Gânglios Espinais/metabolismo , Ratos Sprague-Dawley , Neuralgia/metabolismo , Neuralgia/genética , Neuralgia/tratamento farmacológico , Analgesia
3.
Cereb Cortex ; 34(13): 63-71, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38696609

RESUMO

To investigate potential correlations between the susceptibility values of certain brain regions and the severity of disease or neurodevelopmental status in children with autism spectrum disorder (ASD), 18 ASD children and 15 healthy controls (HCs) were recruited. The neurodevelopmental status was assessed by the Gesell Developmental Schedules (GDS) and the severity of the disease was evaluated by the Autism Behavior Checklist (ABC). Eleven brain regions were selected as regions of interest and the susceptibility values were measured by quantitative susceptibility mapping. To evaluate the diagnostic capacity of susceptibility values in distinguishing ASD and HC, the receiver operating characteristic (ROC) curve was computed. Pearson and Spearman partial correlation analysis were used to depict the correlations between the susceptibility values, the ABC scores, and the GDS scores in the ASD group. ROC curves showed that the susceptibility values of the left and right frontal white matter had a larger area under the curve in the ASD group. The susceptibility value of the right globus pallidus was positively correlated with the GDS-fine motor scale score. These findings indicated that the susceptibility value of the right globus pallidus might be a viable imaging biomarker for evaluating the neurodevelopmental status of ASD children.


Assuntos
Transtorno do Espectro Autista , Encéfalo , Ferro , Imageamento por Ressonância Magnética , Humanos , Transtorno do Espectro Autista/diagnóstico por imagem , Masculino , Feminino , Criança , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Ferro/metabolismo , Ferro/análise , Pré-Escolar , Mapeamento Encefálico/métodos , Substância Branca/diagnóstico por imagem , Globo Pálido/diagnóstico por imagem
4.
Cancer Imaging ; 24(1): 63, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773670

RESUMO

BACKGROUND: Accurate segmentation of gastric tumors from CT scans provides useful image information for guiding the diagnosis and treatment of gastric cancer. However, automated gastric tumor segmentation from 3D CT images faces several challenges. The large variation of anisotropic spatial resolution limits the ability of 3D convolutional neural networks (CNNs) to learn features from different views. The background texture of gastric tumor is complex, and its size, shape and intensity distribution are highly variable, which makes it more difficult for deep learning methods to capture the boundary. In particular, while multi-center datasets increase sample size and representation ability, they suffer from inter-center heterogeneity. METHODS: In this study, we propose a new cross-center 3D tumor segmentation method named Hierarchical Class-Aware Domain Adaptive Network (HCA-DAN), which includes a new 3D neural network that efficiently bridges an Anisotropic neural network and a Transformer (AsTr) for extracting multi-scale context features from the CT images with anisotropic resolution, and a hierarchical class-aware domain alignment (HCADA) module for adaptively aligning multi-scale context features across two domains by integrating a class attention map with class-specific information. We evaluate the proposed method on an in-house CT image dataset collected from four medical centers and validate its segmentation performance in both in-center and cross-center test scenarios. RESULTS: Our baseline segmentation network (i.e., AsTr) achieves best results compared to other 3D segmentation models, with a mean dice similarity coefficient (DSC) of 59.26%, 55.97%, 48.83% and 67.28% in four in-center test tasks, and with a DSC of 56.42%, 55.94%, 46.54% and 60.62% in four cross-center test tasks. In addition, the proposed cross-center segmentation network (i.e., HCA-DAN) obtains excellent results compared to other unsupervised domain adaptation methods, with a DSC of 58.36%, 56.72%, 49.25%, and 62.20% in four cross-center test tasks. CONCLUSIONS: Comprehensive experimental results demonstrate that the proposed method outperforms compared methods on this multi-center database and is promising for routine clinical workflows.


Assuntos
Imageamento Tridimensional , Redes Neurais de Computação , Neoplasias Gástricas , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Imageamento Tridimensional/métodos , Tomografia Computadorizada por Raios X/métodos , Aprendizado Profundo
5.
J Mater Chem B ; 12(20): 4833-4842, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38647018

RESUMO

Ultrasmall iron oxide nanoparticles (USIO NPs) are expected to become the next generation T1 contrast agents; however, their diagnostic and therapeutic potential for primary brain tumors (such as glioblastoma multiforme, GBM) is yet to be explored. At present, the main challenge is the effective hindering of biological barriers, including the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). Herein, we aimed to investigate whether the USIO NPs, in combination with MR-guided focused ultrasound (MRgFUS), could intensify MR imaging of GBM. In this study, we presented zwitterionic USIO NPs for enhanced MR imaging of both xenografted and orthotopic GBM mouse models. We first synthesized citric-stabilized USIO NPs with a size of 3.19 ± 0.76 nm, modified with ethylenediamine, and decorated with 1,3-propanesultone (1,3-PS) to form USIO NPs-1,3-PS. The obtained USIO NPs-1,3-PS exhibited good cytocompatibility and cellular uptake efficiency. MRgFUS, in combination with microbubbles, provided a non-invasive and safe technique for BBB opening, which, in turn, promoted the delivery of USIO NPs-1,3-PS in orthotopic GBM. This developed USIO NP nanoplatform may improve the precision imaging of solid tumors and therapeutic efficacy in the central nervous system.


Assuntos
Neoplasias Encefálicas , Meios de Contraste , Glioblastoma , Nanopartículas Magnéticas de Óxido de Ferro , Imageamento por Ressonância Magnética , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Animais , Camundongos , Humanos , Nanopartículas Magnéticas de Óxido de Ferro/química , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Meios de Contraste/química , Camundongos Nus , Tamanho da Partícula , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C
6.
Biomater Sci ; 12(10): 2705-2716, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38607326

RESUMO

Developing effective nanomedicines to cross the blood-brain barrier (BBB) for efficient glioma theranostics is still considered to be a challenging task. Here, we describe the development of macrophage membrane (MM)-coated nanoclusters (NCs) of ultrasmall iron oxide nanoparticles (USIO NPs) with dual pH- and reactive oxygen species (ROS)-responsivenesses for magnetic resonance (MR) imaging and chemotherapy/chemodynamic therapy (CDT) of orthotopic glioma. Surface citrate-stabilized USIO NPs were solvothermally synthesized, sequentially modified with ethylenediamine and phenylboronic acid, and cross-linked with gossypol to form gossypol-USIO NCs (G-USIO NCs), which were further coated with MMs. The prepared MM-coated G-USIO NCs (G-USIO@MM NCs) with a mean size of 99.9 nm display tumor microenvironment (TME)-responsive gossypol and Fe release to promote intracellular ROS production and glutathione consumption. With the MM-mediated BBB crossing and glioma targeting, the G-USIO@MM NCs can specifically inhibit orthotopic glioma in vivo through the gossypol-mediated chemotherapy and Fe-mediated CDT. Meanwhile, USIO NPs can be dissociated from the NCs under the TME, thus allowing for effective T1-weighted glioma MR imaging. The developed G-USIO@MM NCs with simple components and drug as a crosslinker are promising for glioma theranostics, and may be extended to tackle other cancer types.


Assuntos
Glioma , Macrófagos , Nanomedicina Teranóstica , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Animais , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas Magnéticas de Óxido de Ferro/química , Imageamento por Ressonância Magnética , Humanos , Linhagem Celular Tumoral , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Espécies Reativas de Oxigênio/metabolismo , Membrana Celular/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos
7.
Lung Cancer ; 189: 107495, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38335691

RESUMO

Non-small cell lung cancers (NSCLC) account for 85 % of total lung cancers. Mutation in EGFRdrives the progress of NSCLSs with high mortality rate. Besides the common mutations in EGFR, which together comprise of 85 % of all EGFR mutations and respond to the targeted therapy of EGFR tyrosine kinase inhibitors (TKIs), many other low-frequency mutations of EGFR are existed in patients. The oncogenic roles and sensitivity of these mutations to EGFR TKIs are not fully understood yet. Here we described two cases of lung adenocarcinoma patients harboring EGFR R776L missense mutation, showed PD and SD after treatment with third-generation EGFR inhibitor, Almonertinib. Chemotherapy afterward showed PR effect in one patient with PSF of 10 months. We also explored the oncogenic feature of single R776L mutation by Ba/F3 isogenic cells and found that, EGFR R776L mutation activates EGFR-related survival signaling pathway in Ba/F3 cells, and they are insensitive to gefitinib, afatinib, and Almonertinib, which consistent with our clinical observation.


Assuntos
Acrilamidas , Neoplasias Pulmonares , Pirimidinas , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Indóis , Mutação , Receptores ErbB/genética
8.
Heliyon ; 10(1): e23432, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38192766

RESUMO

Intussusception in adults is a rare surgical emergency. Unlike in children, most adult intussusceptions arise from a pathological lead point. Ileal intussusception caused by a submucosal liposarcoma is a particularly rare phenomenon. This report describes the diagnosis and management of adult ileal intussusception secondary to submucosal liposarcoma in adult to provide a reference for future clinical work. A 64-year-old female presented to the emergency department with worsening abdominal pain associated with an 8 h history of intermittent vomiting. Based on physical examination, laboratory investigations, and computed tomography, the most likely diagnosis was ileal intussusception secondary to liposarcoma. Thus, emergency laparotomy was performed. During exploration, an ileal invagination was visualised approximately 30 cm from the ileocecal valve, and a flexible polypoid mass was palpable at the lead point of the intussusception. Subsequently, the patient underwent radical resection of pathological tissues with a primary end-to-end ileal anastomosis. Histopathological examination revealed a well-differentiated submucosal liposarcoma. Postoperatively, the patient recovered uneventfully and was doing well at the 6-month follow-up in the outpatient clinic. Thus, clinicians should consider the origin of submucosal liposarcomas in adult with intussusception. Once ileal intussusception secondary to submucosal liposarcoma is diagnosed, timely radical resection is recommended.

10.
J Transl Med ; 22(1): 107, 2024 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-38279111

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. This study aimed to construct immune-related long non-coding RNAs (lncRNAs) signature and radiomics signature to probe the prognosis and immune infiltration of GBM patients. METHODS: We downloaded GBM RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) project database, and MRI data were obtained from The Cancer Imaging Archive (TCIA). Then, we conducted a cox regression analysis to establish the immune-related lncRNAs signature and radiomics signature. Afterward, we employed a gene set enrichment analysis (GSEA) to explore the biological processes and pathways. Besides, we used CIBERSORT to estimate the abundance of tumor-infiltrating immune cells (TIICs). Furthermore, we investigated the relationship between the immune-related lncRNAs signature, radiomics signature and immune checkpoint genes. Finally, we constructed a multifactors prognostic model and compared it with the clinical prognostic model. RESULTS: We identified four immune-related lncRNAs and two radiomics features, which show the ability to stratify patients into high-risk and low-risk groups with significantly different survival rates. The risk score curves and Kaplan-Meier curves confirmed that the immune-related lncRNAs signature and radiomics signature were a novel independent prognostic factor in GBM patients. The GSEA suggested that the immune-related lncRNAs signature were involved in L1 cell adhesion molecular (L1CAM) interactions and the radiomics signature were involved signaling by Robo receptors. Besides, the two signatures was associated with the infiltration of immune cells. Furthermore, they were linked with the expression of critical immune genes and could predict immunotherapy's clinical response. Finally, the area under the curve (AUC) (0.890,0.887) and C-index (0.737,0.817) of the multifactors prognostic model were greater than those of the clinical prognostic model in both the training and validation sets, indicated significantly improved discrimination. CONCLUSIONS: We identified the immune-related lncRNAs signature and tradiomics signature that can predict the outcomes, immune cell infiltration, and immunotherapy response in patients with GBM.


Assuntos
Glioblastoma , RNA Longo não Codificante , Adulto , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , RNA Longo não Codificante/genética , Radiômica , Prognóstico , Área Sob a Curva , Microambiente Tumoral/genética
12.
Artigo em Inglês | MEDLINE | ID: mdl-38082801

RESUMO

Accurate segmentation of gastric tumors from computed tomography (CT) images provides useful image information for guiding the diagnosis and treatment of gastric cancer. Researchers typically collect datasets from multiple medical centers to increase sample size and representation, but this raises the issue of data heterogeneity. To this end, we propose a new cross-center 3D tumor segmentation method named unsupervised scale-aware and boundary-aware domain adaptive network (USBDAN), which includes a new 3D neural network that efficiently bridges an Anisotropic neural network and a Transformer (AsTr) for extracting multi-scale features from the CT images with anisotropic resolution, and a scale-aware and boundary-aware domain alignment (SaBaDA) module for adaptively aligning multi-scale features between two domains and enhancing tumor boundary drawing based on location-related information drawn from each sample across all domains. We evaluate the proposed method on an in-house CT image dataset collected from four medical centers. Our results demonstrate that the proposed method outperforms several state-of-the-art methods.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico por imagem , Anisotropia , Conscientização , Fontes de Energia Elétrica , Hospitais
13.
Front Med (Lausanne) ; 10: 1271687, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38098850

RESUMO

Objective: To compare the performance of radiomics-based machine learning survival models in predicting the prognosis of glioblastoma multiforme (GBM) patients. Methods: 131 GBM patients were included in our study. The traditional Cox proportional-hazards (CoxPH) model and four machine learning models (SurvivalTree, Random survival forest (RSF), DeepSurv, DeepHit) were constructed, and the performance of the five models was evaluated using the C-index. Results: After the screening, 1792 radiomics features were obtained. Seven radiomics features with the strongest relationship with prognosis were obtained following the application of the least absolute shrinkage and selection operator (LASSO) regression. The CoxPH model demonstrated that age (HR = 1.576, p = 0.037), Karnofsky performance status (KPS) score (HR = 1.890, p = 0.006), radiomics risk score (HR = 3.497, p = 0.001), and radiomics risk level (HR = 1.572, p = 0.043) were associated with poorer prognosis. The DeepSurv model performed the best among the five models, obtaining C-index of 0.882 and 0.732 for the training and test set, respectively. The performances of the other four models were lower: CoxPH (0.663 training set / 0.635 test set), SurvivalTree (0.702/0.655), RSF (0.735/0.667), DeepHit (0.608/0.560). Conclusion: This study confirmed the superior performance of deep learning algorithms based on radiomics relative to the traditional method in predicting the overall survival of GBM patients; specifically, the DeepSurv model showed the best predictive ability.

14.
ACS Nano ; 17(23): 23889-23902, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38006397

RESUMO

Development of a nanoscale drug delivery system that can simultaneously exert efficient tumor therapeutic efficacy while creating the desired antitumor immune responses is still challenging. Herein, we report the use of a manganese dioxide (MnO2)-entrapping dendrimer nanocarrier to codeliver glucose oxidase (GOx) and cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING) for improved tumor chemodynamic/starvation/immune therapy. Methoxy poly(ethylene glycol) (mPEG)- and phenylboronic acid (PBA)-modified generation 5 (G5) poly(amidoamine) dendrimers were first synthesized and then entrapped with MnO2 nanoparticles (NPs) to generate the hybrid MnO2@G5-mPEG-PBA (MGPP) NPs. The created MGPP NPs with an MnO2 core size of 2.8 nm display efficient glutathione depletion ability, and a favorable Mn2+ release profile under a tumor microenvironment mimetic condition to enable Fenton-like reaction and T1-weighted magnetic resonance (MR) imaging. We show that the MGPP-mediated GOx delivery facilitates enhanced chemodynamic/starvation therapy of cancer cells in vitro, and further codelivery of cGAMP can effectively trigger immunogenic cell death (ICD) to strongly promote the maturation of dendritic cells. In a bilateral mouse colorectal tumor model, the dendrimer delivery nanosystem elicits a potent antitumor performance with a strong abscopal effect, greatly improving the overall mouse survival rate. Importantly, the dendrimer-mediated codelivery not only allows the coordination of Mn2+ with GOx and cGAMP for respective chemodynamic/starvation-triggered ICD and augmented STING activation to boost systemic antitumor immune responses, but also enables T1-weighted tumor MR imaging, potentially serving as a promising nanoplatform for enhanced antitumor therapy with desired immune responses.


Assuntos
Neoplasias Colorretais , Dendrímeros , Nanopartículas , Neoplasias , Animais , Camundongos , Compostos de Manganês/farmacologia , Nucleotídeos , Óxidos , Imageamento por Ressonância Magnética , Glucose Oxidase , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/tratamento farmacológico , Modelos Animais de Doenças , Espectroscopia de Ressonância Magnética , Microambiente Tumoral
15.
Res Sq ; 2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37886453

RESUMO

We previously reported functional Piezo1 expression in Schwann cells of the peripheral nervous system. This study is designed to further investigate the role of Schwann cell Piezo1 in peripheral nociception. We first developed an adeno-associated viral (AAV) vector that has primary Schwann cell tropism after delivery into the sciatic nerve. This was achieved by packing AAV-GFP transcribed by a hybrid CMV enhancer/chicken ß-actin (CBA) promoter using a capsid AAVolig001 to generate AAVolig001-CBA-GFP. Five weeks after intrasciatic injection of AAVolig001-CBA-GFP in naïve rats, GFP expression was detected selectively in the Schwann cells of the sciatic nerve. A short hairpin RNA against rat Piezo1 (PZ1shRNA) was designed that showed efficient physical and functional knockdown of Piezo1 in NG108 neuronal cells. A dual promoter and bidirectional AAV encoding a U6-driven PZ1shRNA and CBA-transcribed GFP was packed with capsid olig001 (AAVolig001-PZ1shRNA), and AAV was injected into unilateral sciatic nerve immediately after induction of common peroneal nerve injury (CPNI). Results showed that the development of mechanical hypersensitivity in the CPNI rats injected with AAVolig001-PZ1shRNA was mitigated, compared to rats subjected with AAVolig001-scramble. Selective in vivo Schwann cell transduction and functional block of Piezo1 channel activity of primary cultured Schwann cells was confirmed. Together, our data demonstrate that 1) AAVolig001 has unique and selective primary tropism to Schwann cells via intrasciatic delivery and 2) Schwann cell Piezo1 contributes to mechanical hypersensitivity following nerve injury.

16.
Radiother Oncol ; 188: 109893, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37659661

RESUMO

BACKGROUND: Whether postoperative radiotherapy (PORT) could improve survival and the role of EBV DNA remains unclear for patients with lymphoepithelial carcinoma of the salivary glands (LECSG). PATIENTS AND METHODS: 360 patients were included. Independent prognostic factors were selected using a Cox proportional hazards model and incorporated into risk stratification. RESULTS: The number of positive lymph nodes (PLNs) ≥ 3 and tumor size ≥ 3 cm were independent factors for PFS in patients with neck dissection (ND). Patients were divided into three groups: high-risk, size ≥ 3 cm&PLNs ≥ 3; intermediate-risk, size < 3 cm&PLNs ≥ 3 or size ≥ 3 cm&PLNs < 3; low-risk, size < 3 cm&PLNs < 3. The 5-year PFS rate of the low-, intermediate- and high-risk patients receiving non-PORT and PORT was 87.9% vs 93.5% (p = 0.12), 41.2% vs 81.1% (p < 0.001), 18.0% vs 51.1% (p = 0.034). N stage was an independent factor for PFS in patients with non-neck dissection (NND) and patients were divided into two groups: low-risk, N0; and high-risk, N1/2. The 5-year PFS rate of the low-risk, and high-risk patients receiving non-PORT and PORT was 77.9% vs 94.3% (p = 0.0019), 21.4% vs 71.3% (p = 0.015). Compared with EBV DNA = 0, the 5-year PFS rate of patients with EBV DNA > 0 was 19.9% vs 91.3% (p < 0.001). In patients with EBV DNA = 0, the 5-year PFS rate of patients with or without PORT was 95.1% vs 92.3% (p = 0.082); while in patients with EBV DNA > 0, the 5-year PFS rate was 37% vs 9.2% (p = 0.0056). CONCLUSIONS: In patients with ND, PLNs < 3&size < 3 cm patients did not benefit from PORT. Detectable EBV DNA after surgery was a negative prognostic factor.

17.
Eur J Med Chem ; 260: 115768, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37683362

RESUMO

Phosphoinositol 3-kinases (PI3Ks) γ and δ are primarily expressed in leukocytes and play crucial roles in regulation of the immune system. Dual inhibition of PI3Kγ/δ has emerged as an effective approach to regulate the tumor microenvironment. Here, we report the exploration of structure-activity relationship optimization which led to the discovery of a potent PI3Kγ/δ dual inhibitor 15u (IHMT-PI3K-455). 15u exhibits strong potency in biochemical and cellular assays and it repolarizes M2 phenotype toward M1 phenotype in THP-1 and BMDM macrophages. In addition, it shows suitable in vivo properties as demonstrated through pharmacokinetic studies in rats and pharmacodynamics properties in a MC38 xenograft model.


Assuntos
Leucócitos , Pirimidinas , Animais , Humanos , Ratos , Modelos Animais de Doenças , Macrófagos , Fenótipo , Pirimidinas/farmacologia
18.
J Pharm Pharmacol Res ; 7(2): 49-61, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37588944

RESUMO

Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are neurodegenerative disorders. Recent studies suggest that cerebral hypoperfusion is an early symptom of AD/ADRD. Dual-specificity protein phosphatase 5 (DUSP5) has been implicated in several pathological conditions, including pulmonary hypertension and cancer, but its role in AD/ADRD remains unclear. The present study builds on our previous findings, demonstrating that inhibition of ERK and PKC leads to a dose-dependent dilation of the middle cerebral artery and penetrating arteriole, with a more pronounced effect in Dusp5 KO rats. Both ERK and PKC inhibitors resulted in a significant reduction of myogenic tone in vessels from Dusp5 KO rats. Dusp5 KO rats exhibited stronger autoregulation of the surface but not deep cortical cerebral blood flow. Inhibition of ERK and PKC significantly enhanced the contractile capacity of vascular smooth muscle cells from both strains. Finally, a significant improvement in learning and memory was observed in Dusp5 KO rats 24 hours after initial training. Our results suggest that altered vascular reactivity in Dusp5 KO rats may involve distinct mechanisms for different vascular beds, and DUSP5 deletion could be a potential therapeutic target for AD/ADRD. Further investigations are necessary to determine the effects of DUSP5 inhibition on capillary stalling, blood-brain barrier permeability, and neurodegeneration in aging and disease models.

19.
Adv Healthc Mater ; 12(26): e2300967, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37470683

RESUMO

Novel strategies to facilitate tumor-specific drug delivery and restore immune attacks remain to be developed to overcome the current limitations of chemotherapy. Herein, a cancer cell membrane (CM)-camouflaged and ultrasmall iron oxide nanoparticles (USIO NPs)-loaded polyethylenimine nanogel (NG) system is reported to co-deliver docetaxel (DTX) and CD47 siRNA (siCD47). The prepared co-delivery system exhibits good colloidal stability, biocompatibility, and r1 relaxivity (1.35 mM-1 s-1 ) and enables redox-responsive release of the loaded DTX in the tumor microenvironment. The NG system realizes homologous targeting delivery of DTX and siCD47 to murine breast cancer cells (4T1 cells) for efficient chemotherapy and gene silencing; thus, inducing immunogenic cell death (ICD) and restoring macrophage phagocytic effect through downregulation of "don't eat me" signals on cancer cells. Likewise, the co-delivery system can also act on macrophages to promote their M1 polarization, which can be combined with DTX-mediated ICD and antibody-mediated immune checkpoint blockade to generate effector T cells for robust chemoimmunotherapy. Further, the USIO NPs-incorporated NG system also allows for magnetic resonance imaging of tumors. The developed biomimetic NG system acting on both cancer cells and macrophages holds a promising potential for macrophage phagocytosis-restored chemoimmunotherapy.


Assuntos
Nanopartículas , Neoplasias , Camundongos , Animais , Nanogéis , Biomimética , Polietilenoimina , Linhagem Celular Tumoral , Docetaxel/farmacologia , Fagocitose , Macrófagos/metabolismo , Imageamento por Ressonância Magnética , Neoplasias/metabolismo , Imunoterapia/métodos , Microambiente Tumoral
20.
ACS Omega ; 8(27): 24663-24672, 2023 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-37457460

RESUMO

The mechanism by which oil recovery can be enhanced by different injection methods of CO2 miscible flooding to alleviate the influence of heterogeneous reservoirs was studied to optimize the injection methods, further improving oil recovery. According to the reservoir heterogeneity characteristics of the TI oil formation group in Lunnan Oilfield, a 1 m double-layer long core was designed and prepared for four CO2 miscible displacement experiments with different injection methods. By analyzing the variation in the injection-production parameters, the displacement effects of different injection methods were compared, and the mechanism of enhanced oil recovery (EOR) was summarized. The results indicate the following. ① The displacement efficiency of the different injection methods lies in the following order. Alternate CO2-water injection, continuous CO2 flooding, cyclic CO2 flooding, and alternate CO2-hydrocarbon gas injection. ② The recovery of crude oil via CO2 miscible flooding in heterogeneous reservoirs relies on both convective diffusion and miscible mass transfer. Convective diffusion depends mainly on control of the displacement pressure differential and the plugging of preferential seepage channels in high-permeability areas, while miscible mass transfer depends mainly on the swept range of the convective diffusion and the degree of miscibility between CO2 and crude oil. ③ To improve the recovery efficiency of CO2 miscible flooding in heterogeneous reservoirs, it is necessary to choose an injection method that optimizes these two aspects.

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