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Gastrointestinal cancers (GICs) are highly prevalent cancers that threaten human health worldwide. The Wnt/ß-catenin signaling pathway has been reported to play a pivotal role in the carcinogenesis of GICs. Numerous interventions targeting the Wnt/ß-catenin signaling in GICs are currently being tested in clinical trials with promising results. Unfortunately, there are no clinically approved drugs that effectively target this pathway. This comprehensive review aims to evaluate the impact of clinical therapies targeting the Wnt/ß-catenin signaling pathway in GICs. By integrating data from bioinformatics databases and recent literature from the past five years, we examine the heterogeneous expression and regulatory mechanisms of Wnt/ß-catenin pathway genes and proteins in GICs. Specifically, we focus on expression patterns, mutation frequencies, and clinical prognoses to understand their implications for treatment strategies. Additionally, we discuss recent clinical trial efforts targeting this pathway. Understanding the inhibitors currently under clinical investigation may help optimize foundational research and clinical strategies. We hope that elucidating the current status of precision therapeutic stratification for patients targeting the Wnt/ß-catenin pathway will guide future innovations in precision medicine for GICs.
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Antineoplásicos , Neoplasias Gastrointestinais , Via de Sinalização Wnt , Humanos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/fisiologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , beta Catenina/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/genética , Terapia de Alvo Molecular/métodosRESUMO
Immune checkpoint inhibitors (ICIs) exhibit compromised therapeutic efficacy in many patients with advanced cancers, particularly those with liver metastases. Much of this incapability can be ascribed as an irresponsiveness resulting from the "cold" hepatic tumor microenvironment that acts as T cell "traps" for which there currently lack countermeasures. We report a novel nanomedicine that converts the hepatic immune microenvironment to a "hot" phenotype by targeting hepatic macrophage-centric T cell elimination. Using the nanomedicine, composed of KIRA6 (an endothelium reticulum stress inhibitor), α-Tocopherol nanoemulsions, and anti-PD1 antibodies, we found its potency in murine models of orthotopic colorectal tumors and hepatic metastases, restoring immune responses and enhancing anti-tumor effects. A post-treatment scrutiny of the immune microenvironment landscape in the liver reveals repolarization of immunosuppressive hepatic macrophages, upregulation of Th1-like effector CD4+ T cells, and rejuvenation of dendritic cells along with CD8+ T cells. These findings suggest adaptations of liver-centric immune milieu modulation strategies to improve the efficacy of ICIs for a variety of "cold" tumors and their liver metastases.
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BACKGROUND: Cytoplasmic male sterility (CMS) has greatly improved the utilization of heterosis in crops due to the absence of functional male gametophyte. The newly developed sporophytic D1 type CMS (CMS-D1) rice exhibits unique characteristics compared to the well-known sporophytic CMS-WA line, making it a valuable resource for rice breeding. RESULTS: In this research, a novel CMS-D1 line named Xingye A (XYA) was established, characterized by small, transparent, and shriveled anthers. Histological and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays conducted on anthers from XYA and its maintainer line XYB revealed that male sterility in XYA is a result of delayed degradation of tapetal cells and abnormal programmed cell death (PCD) of microspores. Transcriptome analysis of young panicles revealed that differentially expressed genes (DEGs) in XYA, compared to XYB, were significantly enriched in processes related to chromatin structure and nucleosomes during the microspore mother cell (MMC) stage. Conversely, processes associated with sporopollenin biosynthesis, pollen exine formation, chitinase activity, and pollen wall assembly were enriched during the meiosis stage. Metabolome analysis identified 176 specific differentially accumulated metabolites (DAMs) during the meiosis stage, enriched in pathways such as α-linoleic acid metabolism, flavone and flavonol biosynthesis, and linolenic acid metabolism. Integration of transcriptomic and metabolomic data underscored the jasmonic acid (JA) biosynthesis pathway was significant enriched in XYA during the meiosis stage compared to XYB. Furthermore, levels of JA, MeJA, OPC4, OPDA, and JA-Ile were all higher in XYA than in XYB at the meiosis stage. CONCLUSIONS: These findings emphasize the involvement of the JA biosynthetic pathway in pollen development in the CMS-D1 line, providing a foundation for further exploration of the molecular mechanisms involved in CMS-D1 sterility.
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Oryza , Infertilidade das Plantas , Pólen , Oryza/genética , Oryza/metabolismo , Oryza/crescimento & desenvolvimento , Pólen/genética , Pólen/crescimento & desenvolvimento , Pólen/metabolismo , Infertilidade das Plantas/genética , Transcriptoma , Perfilação da Expressão Gênica , Metabolômica , Metaboloma , Regulação da Expressão Gênica de Plantas , MeioseRESUMO
Aging and regeneration represent complex biological phenomena that have long captivated the scientific community. To fully comprehend these processes, it is essential to investigate molecular dynamics through a lens that encompasses both spatial and temporal dimensions. Conventional omics methodologies, such as genomics and transcriptomics, have been instrumental in identifying critical molecular facets of aging and regeneration. However, these methods are somewhat limited, constrained by their spatial resolution and their lack of capacity to dynamically represent tissue alterations. The advent of emerging spatiotemporal multi-omics approaches, encompassing transcriptomics, proteomics, metabolomics, and epigenomics, furnishes comprehensive insights into these intricate molecular dynamics. These sophisticated techniques facilitate accurate delineation of molecular patterns across an array of cells, tissues, and organs, thereby offering an in-depth understanding of the fundamental mechanisms at play. This review meticulously examines the significance of spatiotemporal multi-omics in the realms of aging and regeneration research. It underscores how these methodologies augment our comprehension of molecular dynamics, cellular interactions, and signaling pathways. Initially, the review delineates the foundational principles underpinning these methods, followed by an evaluation of their recent applications within the field. The review ultimately concludes by addressing the prevailing challenges and projecting future advancements in the field. Indubitably, spatiotemporal multi-omics are instrumental in deciphering the complexities inherent in aging and regeneration, thus charting a course toward potential therapeutic innovations.
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Envelhecimento , Genômica , Proteômica , Medicina Regenerativa , Envelhecimento/fisiologia , Humanos , Medicina Regenerativa/métodos , Medicina Regenerativa/tendências , Genômica/métodos , Proteômica/métodos , Metabolômica/métodos , Epigenômica/métodos , MultiômicaRESUMO
MAIN CONCLUSION: dnal7, a novel allelic variant of the OsHSP40, affects rice plant architecture and grain yield by coordinating auxins, cytokinins, and gibberellic acids. Plant height and leaf morphology are the most important traits of the ideal plant architecture (IPA), and discovering related genes is critical for breeding high-yield rice. Here, a dwarf and narrow leaf 7 (dnal7) mutant was identified from a γ-ray treated mutant population, which exhibits pleiotropic effects, including dwarfing, narrow leaves, small seeds, and low grain yield per plant compared to the wild type (WT). Histological analysis showed that the number of veins and the distance between adjacent small veins (SVs) were significantly reduced compared to the WT, indicating that DNAL7 controls leaf size by regulating the formation of veins. Map-based cloning and transgenic complementation revealed that DNAL7 is allelic to NAL11, which encodes OsHSP40, and the deletion of 2 codons in dnal7 destroyed the His-Pro-Asp (HPD) motif of OsHSP40. In addition, expression of DNAL7 in both WT and dnal7 gradually increased with the increase of temperature in the range of 27-31 °C. Heat stress significantly affected the seedling height and leaf width of the dnal7 mutant. A comparative transcriptome analysis of WT and dnal7 revealed that DNAL7 influenced multiple metabolic pathways, including plant hormone signal transduction, carbon metabolism, and biosynthesis of amino acids. Furthermore, the contents of the cytokinins in leaf blades were much higher in dnal7 than in the WT, whereas the contents of auxins were lower in dnal7. The contents of bioactive gibberellic acids (GAs) including GA1, GA3, and GA4 in shoots were decreased in dnal7. Thus, DNAL7 regulates rice plant architecture by coordinating the balance of auxins, cytokinins, and GAs. These results indicate that OsHSP40 is a pleiotropic gene, which plays an important role in improving rice yield and plant architecture.
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Giberelinas , Oryza , Oryza/metabolismo , Alelos , Melhoramento Vegetal , Citocininas/metabolismo , Grão Comestível/genética , Ácidos Indolacéticos/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Folhas de Planta/metabolismoRESUMO
Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aß accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.
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Doença de Alzheimer , Vasos Linfáticos , Humanos , Camundongos , Animais , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Cilostazol , Donepezila , Acetilcolinesterase , Sistema Linfático/patologia , Encéfalo/patologia , DrenagemRESUMO
OBJECTIVE: Pulp regeneration with bioactive dentin-pulp complex has been a research hotspot in recent years. Stem cell therapy provided an interest strategy to regenerate the dental-pulp complex. Hence, this study aimed to evaluate the effects of photosensitive gelatin methacrylate (GelMA) hydrogel encapsulating dental pulp stem cells (DPSCs) and silver nanoparticles (AgNPs) for dental pulp regeneration in vitro. METHODS: First, the AgNPs@GelMA hydrogels were prepared by lithium phenyl-2,4,6-trimethyl-benzoyl phosphinate (LAP) initiation via blue-light emitting diode light. The physical and chemical properties of AgNPs@GelMA hydrogels were comprehensively analysed via scanning electron microscopy (SEM), and mechanical characterisation, such as swelling ability, degradation properties, and AgNP release profile. Then, AgNPs@GelMA hydrogels encapsulated DPSCs were used to establish an AgNPs@GelMA biomimetic complex, further analysing its biocompatibility, antibacterial properties, and angiogenic capacity in vitro. RESULTS: The results indicated that GelMA hydrogels demontrated optimal characteristics with a monomer:LAP ratio of 16:1. The physico-chemical properties of AgNPs@GelMA hydrogels did not change significantly after loading with AgNPs. There was no significant difference in AgNP release rate amongst different concentrations of AgNPs@GelMA hydrogels. Fifty to 200 µg/mL AgNPs@GelMA hydrogels could disperse E faecalis biofilm and reduce its metabolic activity . Furthermore, cell proliferation was arrested in 100 and 200 µg/mL AgNPs@GelMA hydrogels. The inhibition of 50 µg/mL AgNPs@GelMA hydrogels on E faecalis biofilm was above 50%, and the cell viability of the hydrogels was higher than 90%. The angiogenesis assay indicated that AgNPs@GelMA hydrogels encapsulating DPSCs could induce the formation of capillary-like structures and express angiogenic markers CD31, vascular endothelial growth factor , and von willebrand factor (vWF) in vitro. CONCLUSIONS: Results of this study indicate that 50 µg/mL AgNPs@GelMA hydrogels encapsulating DPSCs had significant antibacterial properties and angiogenic capacity, which could provide a significant experimental basis for the regeneration of the dentin-pulp complex.
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Polpa Dentária , Gelatina , Hidrogéis , Nanopartículas Metálicas , Regeneração , Prata , Células-Tronco , Polpa Dentária/citologia , Polpa Dentária/efeitos dos fármacos , Humanos , Hidrogéis/química , Nanopartículas Metálicas/uso terapêutico , Células-Tronco/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Gelatina/química , Metacrilatos/química , Antibacterianos/farmacologia , Microscopia Eletrônica de Varredura , Proliferação de Células/efeitos dos fármacosRESUMO
PURPOSE: Thyroid-associated ophthalmopathy (TAO) may result in increased metabolism and abnormalities in microcirculation. The fractal dimension (Df) of retinal vessels has been shown to be related to the pathology of a number of ophthalmic disorders, but it hasn't been investigated in TAO. METHODS: We analyzed 1078 participants aged 18 to 72 (548 healthy volunteers and 530 TAO). Images were captured using a non-mydriatic 45-degree fundus camera. Baseline retinal characteristics, such as vessel width, tortuosity, and Df were measured using semiautomated software from fundus images. The average retinal parameters were compared between the two groups. The receiver operation curve (ROC) was used to assess the diagnostic efficacy of various retinal vascular parameters for TAO. RESULTS: Despite controlling for potential confounding variables, Df, vessel width, and tortuosity significantly increased in TAO compared to healthy volunteers. Compared to active TAO, patients in the inactive phase had a larger retinal venous caliber (p < 0.05), but there was no difference in Df or arterial caliber. Moderate and severe cases had a higher Df compared with mild cases (EUGOGO guidelines). The area under the ROC for Df, tortuosity, and vascular caliber in the diagnosis of TAO was 0.904 (95% CI: 0.884-0.924), 0.638 (95% CI: 0.598-0.679), and 0.617 (95% CI: 0.576-0.658), respectively. CONCLUSIONS: Due to its accessibility, affordability, and non-invasive nature, retinal vascular Df may serve as a surrogate marker for TAO and might be used to identify severe cases. With relatively high diagnostic performance, the Df is of some utility for the detection of TAO.
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Inteligência Artificial , Oftalmopatia de Graves , Vasos Retinianos , Humanos , Adulto , Oftalmopatia de Graves/diagnóstico , Oftalmopatia de Graves/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Feminino , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/patologia , Idoso , Adulto Jovem , AdolescenteRESUMO
Obesity often leads to severe medical complications. However, existing FDA-approved medications to combat obesity have limited effectiveness in reducing adiposity and often cause side effects. These medications primarily act on the central nervous system or disrupt fat absorption through the gastrointestinal tract. Adipose tissue enlargement involves adipose hyperplasia and hypertrophy, both of which correlate with increased reactive oxygen species (ROS) and hyperactivated X-box binding protein 1 (XBP1) in (pre)adipocytes. In this study, we demonstrate that KT-NE, a nanoemulsion loaded with the XBP1 inhibitor KIRA6 and α-Tocopherol, simultaneously alleviates aberrant endoplasmic reticulum stress and oxidative stress in (pre)adipocytes. As a result, KT-NE significantly inhibits abnormal adipogenic differentiation, reduces lipid droplet accumulation, restricts lipid droplet transfer, impedes obesity progression, and lowers the risk of obesity-associated non-alcoholic fatty liver disease in female mice with obesity. Furthermore, diverse administration routes of KT-NE impact its in vivo biodistribution and contribute to localized and/or systemic anti-obesity effectiveness.
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Adiposidade , Obesidade , Feminino , Animais , Camundongos , Hiperplasia/metabolismo , Distribuição Tecidual , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Hipertrofia/patologia , Dieta Hiperlipídica/efeitos adversosRESUMO
Systemic lupus erythematosus (SLE) predominantly affects child-bearing women, leading to an elevated risk of maternal and fetal complications and adverse pregnancy outcomes. Since some medications can cross the placental barrier that persist a threat to both mother and fetus, the risk-benefit ratio of SLE medications should be taken into consideration during pregnancy. Calcineurin inhibitor (CNI), mainly including cyclosporin A, tacrolimus, and voclosporin, is a category of immunosuppressive agents that inhibit calcium/calmodulin-dependent phosphatase calcineurin to block T cell activation. Based on the current clinical evidence, CNI is an alternative in pregnant SLE patients with persistent disease activity (especially lupus nephritis patients) and non-responders to azathioprine. However, there is no comprehensive review that summarizes the efficacy and safety profile of CNI for SLE management during pregnancy. This review presents a summary on the utilization of CNI for SLE management during pregnancy, including the mechanism of action, gestational amelioration of lupus flare, and the balance of maternal benefit-fetal risk, which may provide more references for the management of SLE pregnancies.
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Lúpus Eritematoso Sistêmico , Complicações na Gravidez , Feminino , Gravidez , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/complicações , Inibidores de Calcineurina/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/etiologia , Placenta , Exacerbação dos Sintomas , Resultado da Gravidez , Estudos RetrospectivosRESUMO
BACKGROUND: Patients with thyroid-associated opthalmopathy (TAO) have widespread white matter (WM) abnormalities in the emotional and cognitive functional regions. However, the topological representation of these WM abnormalities and the network-level structural aberrations underlying TAO and concomitant affective disorders are still unclear. METHODS: We used probabilistic diffusion tractography and graph theory to investigate brain network topology in 37 active, 35 inactive TAO patients and 23 healthy controls. Then, we evaluated the partial correlations between network topological metrics and clinical parameters. RESULTS: For global topology, only active TAO patients exhibited significantly decreased global (Eglob) and local (Eloc) efficiency compared with controls, while no significant difference was observed between active and inactive TAO patients. For regional topology, we found a significantly decreased nodal efficiency in the left orbital superior frontal gyrus (ORBsup), medial orbital superior frontal gyrus (ORBsupmed), hippocampus and amygdala in active TAO patients compared with inactive ones. Intriguingly, Eglob, Eloc, and nodal efficiency of left ORBsup, ORBsupmed, olfactory cortex, gyrus rectus, hippocampus, right parahippocampal gyrus and amygdala had significantly positive correlations with anxiety/depression scores, bilateral exophthalmos and intraocular pressure in active TAO patients, while no significant correlation was observed in inactive TAO patients. LIMITATIONS: No longitudinal follow-up. CONCLUSIONS: WM networks of TAO are characterized by decreased local specialization and global integration in the active phase, and decreased nodal efficiency highly related to anxiety and depression in the emotional and cognitive regions. Our findings provide new insight regarding the neurobiological mechanisms of TAO and contribute to the treatment of concomitant affective disorders.
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Depressão , Oftalmopatia de Graves , Humanos , Depressão/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imagem de Tensor de Difusão , AnsiedadeRESUMO
Spinal cord injury (SCI) commonly induces nerve damage and nerve cell degeneration. In this work, a novel dental pulp stem cells (DPSCs) encapsulated thermoresponsive injectable hydrogel with sustained hydrogen sulfide (H2S) delivery is demonstrated for SCI repair. For controlled and sustained H2S gas therapy, a clinically tested H2S donor (JK) loaded octysilane functionalized mesoporous silica nanoparticles (OMSNs) are incorporated into the thermosensitive hydrogel made from Pluronic F127 (PF-127). The JK-loaded functionalized MSNs (OMSF@JK) promote preferential M2-like polarization of macrophages and neuronal differentiation of DPSCs in vitro. OMSF@JK incorporated PF-127 injectable hydrogel (PF-OMSF@JK) has a soft consistency similar to that of the human spinal cord and thus, shows a high cytocompatibility with DPSCs. The cross-sectional micromorphology of the hydrogel shows a continuous porous structure. Last, the PF-OMSF@JK composite hydrogel considerably improves the in vivo SCI regeneration in Sprague-Dawley rats through a reduction in inflammation and neuronal differentiation of the incorporated stem cells as confirmed using western blotting and immunohistochemistry. The highly encouraging in vivo results prove that this novel design on hydrogel is a promising therapy for SCI regeneration with the potential for clinical translation.
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Hidrogéis , Traumatismos da Medula Espinal , Ratos , Animais , Humanos , Ratos Sprague-Dawley , Hidrogéis/química , Estudos Transversais , Polpa Dentária , Traumatismos da Medula Espinal/tratamento farmacológico , Células-Tronco , Medula EspinalRESUMO
As an efficient, non-invasive, low-side-effect, and highly selective cancer therapy, photodynamic therapy (PDT) is used to treat various malignant tumors. However, the inefficiency of dealing with deep tumors and metastatic lesions highly limits the use of PDT. Immunogenic cell death (ICD) is a particular form of tumor cell death that could elicit a tumor-special immune response, leading to a systemic anti-tumor effect and providing therapeutic benefits for metastatic lesions. In this regard, it is crucial to enhance the ability of PDT to induce ICD. Luckily, advanced nanotechnology created many promising ways to improve the immunogenicity of PDT and achieve photoimmunotherapy. This review summarizes the emerging strategies for triggering immunogenic cell death via nanoplatform-enhanced PDT, with particular emphasis on their advantages in photoimmunotherapy. We highlight the nanoplatforms classified according to the basic principles of photodynamic therapy and immunogenic cell death, which provides a valuable reference for the design of nanoplatform for photoimmunotherapy. In addition, we also discuss the current situation and prospect of nano-based photoimmunotherapy in clinical studies.
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Neoplasias , Fotoquimioterapia , Humanos , Morte Celular Imunogênica , Fototerapia , Neoplasias/tratamento farmacológico , Imunoterapia , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologiaRESUMO
Embryo selection is a key point of in vitro fertilization (IVF). The most commonly used method for embryo selection is morphological assessment. However, it is sometimes inaccurate. Follicular fluid (FF) contains a complex mixture of proteins that are essential for follicle development and oocyte maturation. Analyzing human FF proteomic profiles and identifying predictive biomarkers might be helpful for evaluating embryo quality. A total of 22 human FF samples were collected from 19 infertile women who underwent IVF/intracytoplasmic sperm injection (ICSI) treatment between October 2021 and November 2021. FFs were grouped into two categories on the basis of the day 3 embryo quality, grade I or II in the hqFF group and grade III in the nhqFF group. FF was analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The key differentially expressed proteins (DEPs) were validated by parallel reaction monitoring (PRM) and enzyme-linked immunosorbent assay (ELISA). Differentially expressed proteins were further analyzed using DAVID software. A total of 558 proteins were identified, of which 50 proteins were differentially expressed in the hqFF versus nhqFF group, including 32 upregulated proteins (> 1.20-fold, P < 0.05) and 18 downregulated proteins (< 0.67-fold, P < 0.05). Bioinformatics analyses showed that the upregulated DEPs were enriched in components of the coagulation and complement systems and negative regulation of peptidase activity, while the downregulated DEPs were enriched in molecular function of extracellular matrix structural and constituent collagen binding. Our results suggested that a number of protein biomarkers in FF were associated with embryo quality. It may help develop an effective and noninvasive method for embryo selection.
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Líquido Folicular , Infertilidade Feminina , Feminino , Humanos , Masculino , Líquido Folicular/química , Infertilidade Feminina/terapia , Infertilidade Feminina/metabolismo , Proteômica , Espectrometria de Massas em Tandem , Sêmen/metabolismo , Fertilização in vitro/métodos , Proteínas/metabolismo , Biomarcadores/metabolismo , Oócitos/metabolismoRESUMO
Breast carcinoma arising from a fibroadenoma is an uncommon entity and is frequently detected incidentally during pathological examination or excisional biopsy of a benign breast tumor. Due to only sporadic cases being reported, evidence-based guidelines are not well-established to date. The present report describes 16 patients diagnosed with breast carcinoma arising within a fibroadenoma in the Third Hospital of Nanchang (Nanchang, China) between January 2019 and December 2021 and discusses the clinicopathological characteristics, imaging findings and treatment. The age of patients at diagnosis ranged between 19 and 58 years and a well-defined asymptomatic mass was the most common clinical presentation. Carcinoma occurring in fibroadenoma generally mimics a benign tumor and potential carcinomatous changes may not be detected. Pathologically, carcinoma in situ was the predominant subtype in the present study. Additionally, ductal carcinoma in situ was more common compared with lobular carcinoma in situ in the present case series. Regarding the molecular phenotypes, the majority of cases were categorized as luminal subtype, although other subtypes such as triple-negative and HER2 positive breast cancer were also identified. In the present study, seven patients were treated with breast-conserving surgery and nine patients were treated with mastectomy. Sentinel lymph node biopsy was performed in all patients and none exhibited axillary node metastasis. Additionally, six patients underwent radiotherapy and two received chemotherapy. During the follow-up, all patients were alive and no evidence of disease relapse was observed. In summary, clinicians should be aware of the possibility of carcinoma within a fibroadenoma, which could alter the therapeutical course. Adequate biopsy or excision should be performed in patients with indicators of malignant transformation in a presumed benign breast tumor.
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BACKGROUND: The diagnosis of thyroid-associated ophthalmopathy (TAO) usually requires a comprehensive examination, including clinical symptoms, radiological examinations, and blood tests. Therefore, cost-effective and noninvasive methods for the detection of TAO are needed. This study aimed to establish a deep learning-based system to detect TAO based on retinal photographs. MATERIALS AND METHODS: The multicenter observational study included retinal photographs taken from TAO patients and normal participants in 2 hospitals in China. Forty-five-degree retinal photographs, centered on the midpoint between the optic disc and the macula, were captured by trained ophthalmologists. The authors first trained a convolutional neural network model to identify TAO using data collected from one hospital. After internal validation, the model was further evaluated in another hospital as an external validation data set. RESULTS: The study included 1182 retinal photographs of 708 participants for model development, and 365 retinal photographs (189 participants) were obtained as the external validation data set. In the internal validation, the area under the receiver operator curve was 0.900 (95% CI: 0.889-0.910) and the accuracy was 0.860 (95% CI: 0.849-0.869). In the external data set, the model reached an area under the curve of 0.747 (95% CI: 0.728-0.763) and achieved an accuracy of 0.709 (95% CI: 0.690-0.724). CONCLUSIONS: Deep learning-based systems may be promising for identifying TAO in normal subjects using retinal fundus photographs. It may serve as a cost-effective and noninvasive method to detect TAO in the future.
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Macrophages are central to the pathogenesis of kidney disease and serve as an effective therapeutic target for kidney injury and fibrosis. Among them, M2-type macrophages have double-edged effects regarding anti-inflammatory effects and tissue repair. Depending on the polarization of the M2 subtypes (M2a or M2c) in the diseased microenvironment, they can either mediate normal tissue repair or drive tissue fibrosis. In renal fibrosis, M2a promotes disease progression through macrophage-to-myofibroblast transition (MMT) cells, while M2c possesses potent anti-inflammatory functions and promotes tissue repair, and is inhibited. The mechanisms underlying this differentiation are complex and are currently not well understood. Therefore, in this study, we first confirmed that M2a-derived MMT cells are responsible for the development of renal fibrosis and demonstrated that the intensity of TGF-ß signaling is a major factor determining the differential polarization of M2a and M2c. Under excessive TGF-ß stimulation, M2a undergoes a process known as MMT cells, whereas moderate TGF-ß stimulation favors the polarization of M2c phenotype macrophages. Based on these findings, we employed targeted nanotechnology to codeliver endoplasmic reticulum stress (ERS) inhibitor (Ceapin 7, Cea or C) and conventional glucocorticoids (Dexamethasone, Dex or D), precisely modulating the ATF6/TGF-ß/Smad3 signaling axis within macrophages. This approach calibrated the level of TGF-ß stimulation on macrophages, promoting their polarization toward the M2c phenotype and suppressing excessive MMT polarization. The study indicates that the combination of ERS inhibitor and a first-line anti-inflammatory drug holds promise as an effective therapeutic approach for renal fibrosis resolution.
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Nefropatias , Humanos , Nefropatias/patologia , Macrófagos , Fator de Crescimento Transformador beta/farmacologia , Fibrose , Anti-Inflamatórios/farmacologiaRESUMO
BACKGROUND: Postoperative nursing can improve the restlessness and gastrointestinal function of patients with tracheal intubation under general anesthesia in digestive surgery. Wide application of various nursing methods and routine nursing in perioperative nursing of patients with general anesthesia in digestive surgery. AIM: To investigate the impact of early postoperative enteral nutrition nursing based on the enhanced recovery after surgery (ERAS) theory on postoperative agitation and gastrointestinal recovery in patients undergoing general anesthesia that experienced tracheal intubation. METHODS: The data of 126 patients with digestive surgery from May 2019 to February 2022 were retrospectively analyzed. According to different nursing methods, they were divided into control group and observation group, with 63 cases in observation group and 63 cases in control group. The patients in the control group had standard perioperative nursing care, whereas those in the observation group got enteral nourishment as soon as possible after surgery in accordance with ERAS theory. Both the rate and quality of gastrointestinal function recovery were compared between the two groups after treatment ended. Postoperative anesthesia-related adverse events were tallied, patients' nutritional statuses were monitored, and the Riker sedation and agitation score (SAS) was used to measure the incidence of agitation. RESULTS: When compared to the control group, the awake duration, spontaneous breathing recovery time, extubation time and postoperative eye-opening time were all considerably shorter (P < 0.05). There was no significant difference in the recovery time of orientation force between the two groups (P > 0.05); however, the observation group had a lower SAS score than the control group (P < 0.05). The recovery time for normal intestinal sounds, the time it took to have the first postoperative exhaust, the time it took to have the first postoperative defecation, and the time it took to have the first postoperative half-fluid feeding were all faster in the observation group than in the control group (P < 0.05); Fasting blood glucose was lower in the observation group compared to the control group (P < 0.05), while the albumin and hemoglobin levels were higher on the first and third postoperative days; however, there was no statistically significant difference in the incidence of anesthesia-related adverse reactions between the two groups (P > 0.05). CONCLUSION: The extremely early postoperative enteral nutrition nursing based on ERAS theory can reduce the degree of agitation, improve the quality of recovery, promote the recovery of gastrointestinal function, and improve the nutritional status of patients in the recovery period after tracheal intubation under general anesthesia.
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Despite significant progress in vaccine development, especially in the fight against viral infections, many unexplored areas remain including innovative adjuvants, diversification of vaccine formulations, and research into the coordination of humoral and cellular immune mechanisms induced by vaccines. Effective coordination of humoral and cellular immunity is crucial in vaccine design. In this study, we used the spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or ovalbumin (OVA) as antigen models and CpG DNA (an activator of toll-like receptor 9, TLR9) as an adjuvant to prepare a multitargeted liposome (LIPO) vaccine. Once equipped with the ability to target lymph nodes (LN) and the endoplasmic reticulum (ER), the LIPO vaccine significantly enhances the cross-presentation ability of antigen-presenting cells (APCs) for exogenous antigens through the ER-associated protein degradation (ERSD) mechanism. Additionally, the vaccine could fine-tune the efficiency of ER-targeted antigen delivery, actively regulating the presentation of exogenous antigen proteins via the major histocompatibility complex (MHC-I) or MHC-II pathways. Immune data from in vivo mouse experiments indicated that the LIPO vaccine effectively stimulated both humoral and cellular immune responses. Furthermore, it triggers immune protection by establishing a robust and persistent germinal center. Moreover, the multifunctionality of this LIPO vaccine extends to the fields of cancer, viruses, and bacteria, providing insights for skilled vaccine design and improvement.
Assuntos
Imunidade Humoral , Vacinas , Animais , Camundongos , Lipossomos/farmacologia , Antígenos , Imunidade Celular , Adjuvantes ImunológicosRESUMO
Arthritis is a syndrome characterized by inflammation in the joints. Triamcinolone acetonide (TA) was used as an anti-inflammatory agent in the treatment of this disease. However, there are limitations to its clinical application, including rapid clearance from the joint cavity, potential joint damage from multiple injections, and adverse joint events. To address these drawbacks, we developed a tunable in situ forming implant loaded with TA. This injectable polymer solution utilized poly (lactic-co-glycolic acid) (PLGA) as an extended-release material. When injected into the joints, the solution solidifies into implants through a solvent exchange in the aqueous environment. The implants demonstrated robust retention at the injection site and released TA over several weeks even months through diffusion and erosion. By adding different proportions of low water-miscible plasticizers, the release period of the drug could be precisely adjusted. The plasticizers-optimized implants exhibited a tough texture, enhancing the therapeutic efficiency and drug safety in vivo. In arthritic model studies, the tunable TA-loaded implants significantly reduced swelling, pain, and motor discoordination, and also showed suppression of arthritis progression to some extent. These findings suggested that TA-loaded ISFI holds promise for managing inflammatory disorders in individuals with arthritis.