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Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates the CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor-erythroid 2-related-2 (Nrf2) is ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8+ T and chimeric antigen receptor (CAR)-T cells under ROS-rich TME. Here, we demonstrated that tumor growth in Nrf2-/- mice was significantly controlled and was reversed by T cell depletion and further confirmed that Nrf2 deficiency in T cells promotes anti-tumor responses using adoptive transfer model of antigen-specific CD8+ T cells. Nrf2-deficient CTLs are resistant to ROS, and their effector functions are sustained in TME. Furthermore, Nrf2 knockdown in human CAR-T cells enhanced the survival and function of intratumoral CAR-T cells in solid tumor xenograft model and effectively controlled tumor growth. ROS-sensing Nrf2 inhibits the anti-tumor T cell responses, indicating that Nrf2 may be a potential target for T cell immunotherapy strategies against solid tumors.
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BACKGROUND: Accurate estimation of implant size before surgery is crucial in preparing for total knee arthroplasty. However, this task is time-consuming and labor-intensive. To alleviate this burden on surgeons, we developed a reliable artificial intelligence (AI) model to predict implant size. METHODS: We enrolled 714 patients with knee osteoarthritis who underwent total knee arthroplasty from March 2010 to February 2014. All surgeries were performed by the same surgeon using implants from the same manufacturer. We collected 1412 knee anteroposterior (AP) and lateral view x-ray images and retrospectively investigated the implant size. We trained the AI model using both AP and lateral images without any clinical or demographic information and performed data augmentation to resolve issues of uneven distribution and insufficient data. Using data augmentation techniques, we generated 500 images for each size of the femur and tibia, which were then used to train the model. Using data augmentation techniques, we generated 500 images for each size of the femur and tibia, which were then used to train the model. We used ResNet-101 and optimized the model with the aim of minimizing the cross-entropy loss function using both the Stochastic Gradient Descent (SGD) and Adam optimizer. RESULTS: The SGD optimizer achieved the best performance in internal validation. The model showed micro F1-score 0.91 for femur and 0.87 for tibia. For predicting within ± one size, micro F1-score was 0.99 for femur and 0.98 for tibia. CONCLUSION: We developed a deep learning model with high predictive power for implant size using only simple x-ray images. This could help surgeons reduce the time and labor required for preoperative preparation in total knee arthroplasty. While similar studies have been conducted, our work is unique in its use of simple x-ray images without any other data, like demographic features, to achieve a model with strong predictive power.
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Artroplastia de Reemplazo de Rodilla , Inteligencia Artificial , Humanos , Artroplastia de Reemplazo de Rodilla/métodos , Artroplastia de Reemplazo de Rodilla/instrumentación , Femenino , Masculino , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Prótesis de la Rodilla , Osteoartritis de la Rodilla/cirugía , Osteoartritis de la Rodilla/diagnóstico por imagen , Fémur/diagnóstico por imagen , Fémur/cirugía , Radiografía/métodos , Tibia/diagnóstico por imagen , Tibia/cirugía , Anciano de 80 o más AñosRESUMEN
BACKGROUND: The escalating utilization of assisted reproductive technology (ART) in response to global infertility rates has spurred research into its complications. Short-term and long-term outcomes have been extensively studied, particularly the neurological concerns surrounding attention-deficit/hyperactivity disorder (ADHD) among ART-conceived children. This study aims investigate the association between ART and ADHD. METHODS: Medline, Embase, Scopus, and Web of Science databases were searched through April 4, 2023. Cohort, case-control, and cross-sectional studies were eligible for inclusion. primary summary measures included the unadjusted relative risk (RR) and adjusted hazard ratio (HR) with 95â¯% confidence intervals. Both fixed-effects and random-effects models were utilized for meta-analysis data pooling to determine the overall effect size. The onset of ADHD in children conceived through ART compared to those conceived naturally. RESULTS: The systematic search yielded 8 studies with 10,176,148 individuals included in the meta-analysis. The meta-analysis revealed a pooled RR of 0.93 (0.68-1.26) for cohort studies and a pooled RR of 0.97 (0.41-2.29) for cross-sectional studies, along with a pooled HR of 1.08 (1.03-1.13) for ADHD in the ART group compared to the non-ART group. CONCLUSION: While this study identifies some potential association between ART and ADHD, the limited effect size and inherent heterogeneity underscore the need for cautious interpretation.
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Type 2 diabetes mellitus (T2DM) and periodontitis (PD) have intricated connections as chronic inflammatory diseases. While the immune response is a key factor that accounts for their association, the underlying mechanisms remain unclear. To gain a deeper understanding of the connection, we conducted research using a multiomics approach. We generated whole genome and methylation profiling array data from the periodontium of PD patients with DM (PDDM) and without DM to confirm genetic and epigenetic changes. Independent bulk and single-cell RNA sequencing data were employed to verify the expression levels of hypo-methylated genes. We observed a gradual rise in C>T base substitutions and hypomethylation in PD and PDDM patients compared with healthy participants. Furthermore, specific genetic and epigenetic alterations were prominently associated with the Fc-gamma receptor-mediated phagocytosis pathway. The upregulation of these genes was confirmed in both the periodontal tissues of PD patients and the pancreatic tissues of T2DM patients. Through single-cell RNA analysis of peripheral blood mononuclear cells, substantial upregulation of Fc-gamma receptors and related genes was particularly identified in monocytes. Our findings suggest that targeting the Fc-gamma signaling pathway in monocytes holds promise as a potential treatment strategy for managing systemic complications associated with diabetes.
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OBJECTIVES: This study aimed to screen oral squamous cell carcinoma (OSCC) diagnostic and prognostic candidates and investigate the potential functions and mechanisms of candidates in the chemoresistance of OSCC cell lines. MATERIALS AND METHODS: Differential expression profiling of lncRNA was performed in a large cohort of OSCC patients from the Cancer Genome Atlas database to identify OSCC diagnostic and prognostic candidates. Taxol resistance in OSCC cell lines was analyzed using MTT assay. OSCC cell lines transfected with EIF3J-DT pcDNA or siRNA were used to determine its regulatory effects on apoptosis, cell cycle distribution and autophagy using flow cytometry and western blot. RESULTS: We identified EIF3J-DT as a candidate for OSCC diagnosis and prognosis. The expression level of EIF3J-DT in OSCC cell lines correlates with taxol resistance. EIF3J-DT silencing attenuated taxol resistance, and EIF3J-DT overexpression enhanced taxol resistance in OSCC cell lines. Silencing of EIF3J-DT reduced taxol resistance by inducing apoptosis, cell cycle arrest, and ATG14-mediated autophagy inhibition in OSCC cell lines. CONCLUSIONS: We found that EIF3J-DT induced chemoresistance by regulating apoptosis, cell cycle, and autophagy in OSCC cell lines, which EIF3J-DT might provide a novel therapeutic approach for OSCC as well as a diagnostic and prognostic factor.
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Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis.
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Degranulación de la Célula , Modelos Animales de Enfermedad , Eosinófilos , Imiquimod , Intestino Delgado , Psoriasis , Receptor Toll-Like 7 , Animales , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 7/genética , Psoriasis/patología , Psoriasis/metabolismo , Ratones , Eosinófilos/metabolismo , Eosinófilos/inmunología , Humanos , Intestino Delgado/patología , Intestino Delgado/metabolismo , Piel/patología , Piel/metabolismo , Inflamación/patología , Inflamación/metabolismo , Ratones Noqueados , Células CACO-2 , Glicoproteínas de MembranaRESUMEN
Obesity is a potential risk factor for meniscal tear (MT). We utilized meta-analysis of observational studies and Mendelian randomization (MR) analyses to elucidate the association between body mass index (BMI) and MT. In meta-analysis, a search was performed on June 27, 2022, using PubMed and Embase databases. Odds ratios and 95% confidence intervals were extracted from included studies. In MR analyses, the research utilized summary-level data on BMI and MT obtained from Genetic Investigation of Anthropometric Traits and the FinnGen Consortium, respectively. In meta-analysis, four studies comprising 826,383 participants were included. The pooled odds ratio of MT in the high BMI group was 1.32 (95% confidence interval, 0.83-2.09), compared with the nonhigh BMI group. The pooled odds ratio in the under 30 group was 1.76 (95% confidence interval, 0.61-5.03). In MR analyses, one standard deviation increase in genetically predicted BMI was associated with meniscus derangement as a chronic subtype of MT (odds ratio, 1.36; 95% confidential interval, 1.17-1.59). We found that a high BMI was not associated with an increased likelihood of MT based on meta-analysis of observational studies; however, by complementing MR analyses, we elucidated the causality of BMI increase on meniscus derangement as a chronic subtype of MT.
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Índice de Masa Corporal , Análisis de la Aleatorización Mendeliana , Obesidad , Estudios Observacionales como Asunto , Lesiones de Menisco Tibial , Humanos , Lesiones de Menisco Tibial/genética , Obesidad/genética , Factores de RiesgoRESUMEN
The association between psoriasis and alcohol consumption has been inconsistent across various studies. However, to the best of our knowledge, no dose-response meta-analysis has been performed to date. This study aims to investigate the association between alcohol consumption and psoriasis. The search was performed on July 27, 2021, using Embase and MEDLINE. The restricted cubic spline analysis was used to perform a dose-response analysis. We identified 3,904 studies, of which 48 studies with 1,702,847 individuals across 24 countries were included. Alcohol consumption was positively associated with psoriasis (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.27-1.70). In addition, a significantly increased OR for psoriasis was observed in males (OR, 1.84; 95% CI, 1.13-3.01) but not in females (OR, 1.22; 95% CI, 0.97-1.54). Based on eight studies, including three cohort and five case-control studies, the analysis revealed that with each additional gram of daily alcohol intake, the OR for psoriasis increased by 4%. We found a positive association between alcohol consumption and psoriasis. The association is more prominent in the group drinking more than 45 g of alcohol per day (3.2 alcoholic drink equivalent).
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Consumo de Bebidas Alcohólicas , Psoriasis , Psoriasis/epidemiología , Humanos , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/efectos adversos , Femenino , Masculino , Factores de Riesgo , Factores Sexuales , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Epilepsy, characterized by recurrent unprovoked seizures, poses significant challenges to affected individuals globally. While several established risk factors for epilepsy exist, the association with cigarette smoking remains debated. This study aims to conduct systematic review and meta-analysis to elucidate the potential association between smoking and the likelihood of epilepsy. METHODS: The search was performed on March 31st, 2023, using the Medline, Embase, Web of Science, Scopus, and ScienceDirect. We included cohort, cross-sectional, and case-control studies in our meta-analysis, conducting subgroup analyses based on smoking history, sex, and epilepsy type to yield specific insights. RESULTS: We identified 2550 studies, of which 17 studies were finally included in this study. The pooled odds ratio of epilepsy was 1.14 (0.96-1.36) in smokers compared to non-smokers. In current smokers compared to non-smokers, the odds ratio was 1.46 (1.13-1.89), while, in former smokers compared to non-smokers, the odds ratio was 1.14 (0.83-1.56). CONCLUSIONS: While the overall association between smoking and epilepsy did not reach statistical significance, a notable association was found among current smokers. The study emphasizes the importance of smoking cessation as a potential preventive measure against epilepsy, especially given the proconvulsive effects of nicotine. Future research should address limitations and explore specific clinical scenarios to enhance our understanding of the complex relationship between cigarette use and epilepsy. SYSTEMATIC REVIEW REGISTRATION: CRD42022342510.
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Epilepsia , Humanos , Estudios Transversales , Epilepsia/epidemiología , Fumadores , Factores de Riesgo , Fumar/efectos adversos , Fumar/epidemiologíaRESUMEN
There has been significant progress in the field of three-dimensional (3D) bioprinting technology, leading to active research on creating bioinks capable of producing structurally and functionally tissue-mimetic constructs. Ti3C2Tx MXene nanoparticles (NPs), promising two-dimensional nanomaterials, are being investigated for their potential in muscle regeneration due to their unique physicochemical properties. In this study, we integrated MXene NPs into composite hydrogels made of gelatin methacryloyl (GelMA) and hyaluronic acid methacryloyl (HAMA) to develop bioinks (namely, GHM bioink) that promote myogenesis. The prepared GHM bioinks were found to offer excellent printability with structural integrity, cytocompatibility, and microporosity. Additionally, MXene NPs within the 3D bioprinted constructs encouraged the differentiation of C2C12 cells into skeletal muscle cells without additional support of myogenic agents. Genetic analysis indicated that representative myogenic markers both for early and late myogenesis were significantly up-regulated. Moreover, animal studies demonstrated that GHM bioinks contributed to enhanced regeneration of skeletal muscle while reducing immune responses in mice models with volumetric muscle loss (VML). Our results suggest that the GHM hydrogel can be exploited to craft a range of strategies for the development of a novel bioink to facilitate skeletal muscle regeneration because these MXene-incorporated composite materials have the potential to promote myogenesis.
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Hidrogeles , Nanopartículas , Nitritos , Elementos de Transición , Ratones , Animales , Hidrogeles/farmacología , Hidrogeles/química , Gelatina/química , Impresión Tridimensional , Glicosaminoglicanos , Músculo Esquelético , Andamios del Tejido/química , Ingeniería de Tejidos/métodosRESUMEN
The importance of lung microbiome changes in developing chronic lung allograft dysfunction (CLAD) after lung transplantation is poorly understood. The lung microbiome-immune interaction may be critical in developing CLAD. In this context, examining alterations in the microbiome and immune cells of the lungs following CLAD, in comparison to the lung condition immediately after transplantation, can offer valuable insights. Four adult patients who underwent lung retransplantation between January 2019 and June 2020 were included in this study. Lung tissues were collected from the same four individuals at two different time points: at the time of the first transplant and at the time of the explantation of CLAD lungs at retransplantation due to CLAD. We analyzed whole-genome sequencing using the Kraken2 algorithm and quantified the cell fractionation from the bulk tissue gene expression profile for each lung tissue. Finally, we compared the differences in lung microbiome and immune cells between the lung tissues of these two time points. The median age of the recipients was 57 years, and most (75%) had undergone lung transplants for idiopathic pulmonary fibrosis. All patients were administered basiliximab for induction therapy and were maintained on three immunosuppressants. The median CLAD-free survival term was 693.5 days, and the median time to redo the lung transplant was 843.5 days. Bacterial diversity was significantly lower in the CLAD lungs than at transplantation. Bacterial diversity tended to decrease according to the severity of the CLAD. Aerococcus, Caldiericum, Croceibacter, Leptolyngbya, and Pulveribacter genera were uniquely identified in CLAD, whereas no taxa were identified in lungs at transplantation. In particular, six taxa, including Croceibacter atlanticus, Caldiserium exile, Dolichospermum compactum, Stappia sp. ES.058, Kinetoplastibacterium sorsogonicusi, and Pulveribacter suum were uniquely detected in CLAD. Among immune cells, CD8+ T cells were significantly increased, while neutrophils were decreased in the CLAD lung. In conclusion, unique changes in lung microbiome and immune cell composition were confirmed in lung tissue after CLAD compared to at transplantation.
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BACKGROUND AND PURPOSE: The optimal blood pressure (BP) control after successful endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) with large vessel occlusion (LVO) remains debatable. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that evaluate the efficacy and safety of standard BP control (with systolic BP ≤180 mm Hg) versus intensive BP control (systolic BP <140 mm Hg) during the 24 hours after successful EVT in AIS with LVO. METHODS: PubMed, Scopus, the Cochrane Central Register of Controlled Trials, and Embase were searched to identify relevant trials. The crude odds ratio (OR) and 95% confidence interval (CI) were calculated and estimates using random-effects models were pooled. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO ID: CRD42023450673). RESULTS: Four RCTs involving 1,559 participants were included. Regarding efficacy outcomes, intensive BP control was associated with a lower likelihood of functional independence (OR: 0.68; 95% CI: 0.51-0.91 for modified Rankin Scale [mRS] ≤2) and walking without assistance (OR: 0.65; 95% CI: 0.53-0.81 for mRS ≤3). For safety outcomes, consistent with the efficacy findings, intensive BP control was significantly associated with severe disability or death (mRS 5 or 6) (OR: 1.34; 95% CI: 1.07-1.69). However, there were no significant differences including all-cause mortality, any intracerebral hemorrhage (ICH), symptomatic ICH, parenchymal hematoma type 2, and stroke recurrence. CONCLUSION: While all four RCTs were conducted to demonstrate the superiority of intensive BP control over standard BP control, standard BP control may be beneficial for the outcome after EVT for AIS with LVO without increasing adverse safety outcomes. Caution should be needed with the application of intensive BP control during the 24 hours following successful recanalization after EVT.
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AIMS: Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. METHODS: Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. RESULTS: SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1ß inhibition. CONCLUSIONS: SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Sirtuinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Sorafenib/farmacología , Sorafenib/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Inflamasomas/metabolismo , Inflamasomas/farmacología , Fosforilación , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sistema de Señalización de MAP Quinasas , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Proliferación Celular , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/farmacología , Sirtuinas/genética , Sirtuinas/metabolismo , Sirtuinas/farmacologíaRESUMEN
The progression of idiopathic pulmonary fibrosis (IPF) is diverse and unpredictable. We identified and validated a new biomarker for IPF progression. To identify a candidate gene to predict progression, we assessed differentially expressed genes in patients with advanced IPF compared with early IPF and controls in three lung sample cohorts. Candidate gene expression was confirmed using immunohistochemistry and Western blotting of lung tissue samples from an independent IPF clinical cohort. Biomarker potential was assessed using an enzyme-linked immunosorbent assay of serum samples from the retrospective validation cohort. We verified that the final candidate gene reflected the progression of IPF in a prospective validation cohort. In the RNA-seq comparative analysis of lung tissues, CD276, COL7A1, CTSB, GLI2, PIK3R2, PRAF2, IGF2BP3, and NUPR1 were up-regulated, and ADAMTS8 was down-regulated in the samples of advanced IPF. Only CTSB showed significant differences in expression based on Western blotting (n = 12; p < 0.001) and immunohistochemistry between the three groups of the independent IPF cohort. In the retrospective validation cohort (n = 78), serum CTSB levels were higher in the progressive group (n = 25) than in the control (n = 29, mean 7.37 ng/mL vs. 2.70 ng/mL, p < 0.001) and nonprogressive groups (n = 24, mean 7.37 ng/mL vs. 2.56 ng/mL, p < 0.001). In the prospective validation cohort (n = 129), serum CTSB levels were higher in the progressive group than in the nonprogressive group (mean 8.30 ng/mL vs. 3.00 ng/mL, p < 0.001). After adjusting for baseline FVC, we found that CTSB was independently associated with IPF progression (adjusted OR = 2.61, p < 0.001). Serum CTSB levels significantly predicted IPF progression (AUC = 0.944, p < 0.001). Serum CTSB level significantly distinguished the progression of IPF from the non-progression of IPF or healthy control.
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Genes Reguladores , Fibrosis Pulmonar Idiopática , Humanos , Estudios Retrospectivos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/genética , Factores de Transcripción , Biomarcadores , Proteínas ADAMTS , Antígenos B7 , Proteínas Portadoras , Proteínas de la Membrana , Colágeno Tipo VIIRESUMEN
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder primarily affecting the voluntary motor nervous system. Several observational studies have provided conflicting results regarding the association between smoking and ALS. Therefore, our objective was to investigate this association through a systematic review, meta-analysis, and dose-response analysis. METHODS: On 16 January 2023, we initially extracted records from medical databases, which included Medline, Embase, Web of Science, Scopus, and ScienceDirect. We included case-control and cohort studies as eligible studies. Subgroup analyses were performed based on sex, study design, and current smoking. Restricted cubic-spline analysis was utilized to assess the dose-response relationship between smoking (pack-years) and ALS. RESULTS: Twenty-eight case-control and four cohort studies met the inclusion criteria. The unadjusted OR for the overall association between smoking and ALS was 1.14 (95% CI: 1.06-1.22, I2=44%, p<0.001), and the adjusted OR (AOR) was 1.12 (95% CI: 1.03-1.21, I2=49%, p=0.009). Subgroup analysis revealed a more pronounced association among current smokers, with an AOR of 1.28 (95% CI: 1.10-1.49, I2=66%, p<0.001) and AOR of 1.28 (95% CI: 1.10-1.48, I2=58%, p=0.001). In the dose-response analysis, the non-linear model revealed an inverted U-shaped curve. CONCLUSIONS: Our study provides evidence of a positive relationship between smoking and the risk of ALS. To mitigate the risk of developing ALS, discontinuing smoking, which is a modifiable risk factor, may be crucial.TRIAL REGISTRATION: The study was registered in PROSPERO.IDENTIFIER: CRD42023388822.
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Current therapeutic approaches for volumetric muscle loss (VML) face challenges due to limited graft availability and insufficient bioactivities. To overcome these limitations, tissue-engineered scaffolds have emerged as a promising alternative. In this study, we developed aligned ternary nanofibrous matrices comprised of poly(lactide-co-ε-caprolactone) integrated with collagen and Ti3C2Tx MXene nanoparticles (NPs) (PCM matrices), and explored their myogenic potential for skeletal muscle tissue regeneration. The PCM matrices demonstrated favorable physicochemical properties, including structural uniformity, alignment, microporosity, and hydrophilicity. In vitro assays revealed that the PCM matrices promoted cellular behaviors and myogenic differentiation of C2C12 myoblasts. Moreover, in vivo experiments demonstrated enhanced muscle remodeling and recovery in mice treated with PCM matrices following VML injury. Mechanistic insights from next-generation sequencing revealed that MXene NPs facilitated protein and ion availability within PCM matrices, leading to elevated intracellular Ca2+ levels in myoblasts through the activation of inducible nitric oxide synthase (iNOS) and serum/glucocorticoid regulated kinase 1 (SGK1), ultimately promoting myogenic differentiation via the mTOR-AKT pathway. Additionally, upregulated iNOS and increased NO- contributed to myoblast proliferation and fiber fusion, thereby facilitating overall myoblast maturation. These findings underscore the potential of MXene NPs loaded within highly aligned matrices as therapeutic agents to promote skeletal muscle tissue recovery.
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BACKGROUND: Lichen striatus (LS) is an acquired skin disorder with a linear pattern along Blaschko's lines. It commonly occurs in childhood, and the lesions spontaneously regress within several months. OBJECTIVES: Although up to 50% of LS cases exhibit hypopigmentation that can persist for several months to years, it is unknown why LS is associated with such a high incidence of hypopigmentation compared to other inflammatory skin diseases. Therefore, this study aimed to analyse the differences in the skin microbiome between LS patients with and without hypopigmentation. METHODS: Differences in skin microbiome were analysed using whole genome sequencing of skin biopsies and subsequent bioinformatics analyses. RESULTS: Some microbes commonly found in hypopigmented skin disorders, including Cutibacterium acnes, were more abundant in patients with LS showing hypopigmentation than in those not showing hypopigmentation. CONCLUSIONS: The skin microbiota may be involved in the development of hypopigmentation in LS and may be considered a treatment target to reduce LS duration and hypopigmentation.
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Hipopigmentación , Microbiota , Humanos , Hipopigmentación/microbiología , Femenino , Masculino , Adulto , Piel/microbiología , Piel/patología , Niño , Adolescente , Persona de Mediana Edad , Adulto Joven , Erupciones Liquenoides/microbiologíaRESUMEN
Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV- associated HNSCC is increasing. The role of tumor microenvironment in viral infection and metastasis needs to be explored further. We studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status. Eight samples for single-cell RNA profiling and six samples for spatial transcriptomics (ST), composed of matched primary tumors (PT) and lymph node metastases (LNMT), were collected from both HPV- negative (HPV- ) and HPV-positive (HPV+ ) patients. Using the 10x Genomics Visium platform, integrative analyses with single-cell RNA sequencing were performed. Intracellular and intercellular alterations were analyzed, and the findings were confirmed using experimental validation and publicly available data set. The HPV+ tissues were composed of a substantial amount of lymphoid cells regardless of the presence or absence of metastasis, whereas the HPV- tissue exhibited remarkable changes in the number of macrophages and plasma cells, particularly in the LNMT. From both single-cell RNA and ST data set, we discovered a central gene, pyruvate kinase muscle isoform 1/2 (PKM2), which is closely associated with the stemness of cancer stem cell-like populations in LNMT of HPV- tissue. The consistent expression was observed in HPV- HNSCC cell line and the knockdown of PKM2 weakened spheroid formation ability. Furthermore, we found an ectopic lymphoid structure morphology and clinical effects of the structure in ST slide of the HPV+ patients and verified their presence in tumor tissue using immunohistochemistry. Finally, the ephrin-A (EPHA2) pathway was detected as important signals in angiogenesis for HPV- patients from single-cell RNA and ST profiles, and knockdown of EPHA2 declined the cell migration. Our study described the distinct cellular composition and molecular alterations in primary and metastatic sites in HNSCC patients based on their HPV status. These results provide insights into HNSCC biology in the context of HPV infection and its potential clinical implications.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas/patología , Virus del Papiloma Humano , Papillomaviridae/genética , Neoplasias de Cabeza y Cuello/genética , Perfilación de la Expresión Génica/métodos , ARN , Microambiente Tumoral/genéticaRESUMEN
Janus kinase (JAK) inhibitors have been recently approved by the FDA and are widely used in the treatment of patients with atopic dermatitis. However, a comprehensive safety profile of JAK inhibitors in patients with atopic dermatitis has not been analysed. This study aimed to establish clinical evidence for the safety of systemic JAK inhibitors in patients with atopic dermatitis. Medline, Embase, Clinicaltrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) and International Clinical Trials Registry Platform (ICTRP) were considered for search databases. Randomized controlled trials reporting the adverse events of systemic therapy in patients with atopic dermatitis were included. The risk of 11 adverse events was compared between the JAK inhibitors and placebo groups. Fourteen randomized controlled trials were analysed published between 2019 and 2022. The JAK inhibitors included in the analysis were abrocitinib (10, 30, 100 and 200 mg), baricitinib (1, 2 and 4 mg) and upadacitinib (7.5, 15 and 30 mg). The risk of herpes zoster, headache, acne, elevated blood creatinine phosphokinase and nausea was significantly increased, but the risk of serious infection, non-melanoma skin cancer (NMSC), malignancies other than NMSC, major adverse cardiovascular event, venous thromboembolism and nasopharyngitis was not increased. This study provides comprehensive clinical evidence on the risk of various adverse events in patients with atopic dermatitis. However, since the follow-up periods of the studies analysed in this review were mostly limited to 16 weeks or less, it is recommended that comprehensive long-term observational studies be conducted to determine any potential adverse events associated with major cardiovascular events or malignancies, which typically have prolonged courses.