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BRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.
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Resistencia a Antineoplásicos , Indoles , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Sulfonamidas , Neoplasias de la Tiroides , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Humanos , Animales , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Indoles/farmacología , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sulfonamidas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Línea Celular Tumoral , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Sorafenib/farmacología , Quinolinas/farmacología , Mutación , Antígenos/metabolismo , Proteoglicanos/metabolismo , Proteínas de la Membrana , Proteoglicanos Tipo Condroitín SulfatoRESUMEN
Gliomas are the most common primary intracranial tumor worldwide. The maintenance of telomeres serves as an important biomarker of some subtypes of glioma. In order to investigate the biological role of RTEL1 in glioma. Relative telomere length (RTL) and RTEL1 mRNA was explored and regression analysis was performed to further examine the relationship of the RTL and the expression of RTEL1 with clinicopathological characteristics of glioma patients. We observed that high expression of RTEL1 is positively correlated with telomere length in glioma tissue, and serve as a poor prognostic factor in TERT wild-type patients. Further in vitro studies demonstrate that RTEL1 promoted proliferation, formation, migration and invasion ability of glioma cells. In addition, in vivo studies also revealed the oncogene role of RTEL1 in glioma. Further study using RNA sequence and phospho-specific antibody microarray assays identified JNK/ELK1 signaling was up-regulated by RTEL1 in glioma cells through ROS. In conclusion, our results suggested that RTEL1 promotes glioma tumorigenesis through JNK/ELK1 cascade and indicate that RTEL1 may be a prognostic biomarker in gliomas.
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Neoplasias Encefálicas , Glioma , Humanos , Glioma/patología , Neoplasias Encefálicas/genética , Transformación Celular Neoplásica/genética , Oncogenes , Biomarcadores , Proliferación Celular , Proteína Elk-1 con Dominio ets/genética , ADN Helicasas/genéticaRESUMEN
Human Toll-like receptor (TLR) family plays a crucial role in immunity and cancer progression. However, the specific role of human Toll-like receptor 4 (TLR4) in kidney renal clear cell carcinoma (KIRC) remains obscure. Thus, we used single-cell RNA sequencing (RNA-seq) and bulk RNA-seq data combined with in vitro studies to evaluate the expression and prognostic value of TLR4 in KIRC. In our study, we observed that TLR4 was over expressed in KIRC tissues compared to normal renal tissues. And the expression of TLR4 was higher in macrophages/monocytes than other cell types. Besides, there is a close association between TLR4 expression and immune cell infiltration (Neutrophils, Macrophages, T cells and B cells) in KIRC. Immunohistochemical staining also showed that TLR4 was overexpressed in inflammatory infiltration renal tissue compared with normal tissue. Meanwhile, high expression of TLR4 exhibited correlations with improved survival, lower tumor grade and stage. Interestingly, the protective significance of TLR4 only showed in female patients (HR = 0.37, P < 0.01), other than male patients (HR = 0.71, P = 0.08) with KIRC. Consistently, KIRC samples with lymph node metastasis showed lower expression of TLR4. Knockdown of TLR4 in 786-O cell line increased cell proliferation and clonogenic capacity. In summary, this study found TLR4 could inhibit the progression of kidney cancer and was associated with improved survival in KIRC. The overexpression of TLR4 in macrophages and the close association between TLR4 and immune cell infiltration also underline the critical role of TLR4 in building the immune microenvironment for kidney cancer. These results may offer insights into the mechanism and immune microenvironment of kidney cancer.
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Carcinoma de Células Renales , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales , Receptor Toll-Like 4 , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Pronóstico , Femenino , Masculino , Línea Celular Tumoral , Persona de Mediana Edad , Proliferación Celular/genética , Macrófagos/metabolismoRESUMEN
Head and neck squamous carcinoma (HNSC) poses a significant public health challenge due to its substantial morbidity. Nevertheless, despite advances in current treatments, the prognosis for HNSC remains unsatisfactory. To address this, single-cell RNA sequencing (RNA-seq) and bulk RNA-seq data combined with in vitro studies were conducted to examine the role of MYO5A (Myosin VA) in HNSC. Our investigation revealed an overexpression of MYO5A in HNSC that promotes HNSC migration in vitro. Remarkably, knockdown of MYO5A suppressed vimentin expression. Furthermore, analyzing the TCGA database evidenced that MYO5A is a risk factor for human papillomavirus positive (HPV+) HNSC (HR = 0.81, P < 0.001). In high MYO5A expression HNSC, there was a low count of tumor infiltrating lymphocytes (TIL), including activated CD4+ T cells, CD8+ T cells, and B cells. Of note, CD4+ T cells and B cells were positively associated with improved HPV+ HNSC outcomes. Correlation analysis demonstrated a decreased level of immunostimulators in high MYO5A-expressing HNSC. Collectively, these findings suggest that MYO5A may promote HNSC migration through vimentin and involve itself in the process of immune infiltration in HNSC, advancing the understanding of the mechanisms and treatment of HNSC.
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Neoplasias de Cabeza y Cuello , Miosina Tipo V , Infecciones por Papillomavirus , Humanos , Vimentina/genética , Neoplasias de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Procesos Neoplásicos , Pronóstico , Linfocitos Infiltrantes de Tumor , Cadenas Pesadas de Miosina/genética , Miosina Tipo V/genéticaRESUMEN
Triple-negative breast cancer (TNBC) represents 10-20 % of all breast cancer (BC) cases and is characterized by poor prognosis. Given the urgent need to improve prognostication and develop specific therapies for TNBC, the identification of new molecular targets is of great importance. MicroRNA (miRNA) has been reported as a valuable and novel molecular target in the progression of TNBC. However, the expression and function of miRNAs in different tumors are heterogeneous. Herein, we first analyzed miRNA data from The Cancer Genome Atlas (TCGA) and surprisedly found that overexpressed miRNAs were associated with poor survival in all breast cancer patients, but the overexpressed miRNAs were associated with better survival in TNBC patients. Based on the heterogeneity of miRNA expression in TNBC, we conducted further analysis using univariate Cox proportional hazard regression models and identified 17 miRNAs with prognostic potential. Subsequently, a multivariate Cox model was employed to create a 3-miRNA prognostic model for predicting overall survival in TNBC patients. The diagnostic model exhibited an area under the curve (AUC) of 0.727, and multivariable Cox regression indicated that each covariate was associated with survival. These data indicate that this model is relatively accurate and robust for risk assessment, which have a certain value for clinical application. In order to explore the network behind the overexpressed miRNAs in TNBC, we established a novel network consisting of lncRNAs, miRNAs, and mRNAs through complete transcriptome data from matched samples in the TCGA database. In this network, IRS-1 appeared to be the top hub gene. Experimental results demonstrated that miR-15b-5p and miR-148a-3p effectively target IRS-1 in vitro, shedding light on the intricate regulatory mechanisms in TNBC mediated by the heterogeneous miRNAs. Besides, miR-148a-3p significantly inhibited cell migration and viability. Overall, this study may add valuable insights into the molecular landscape of TNBC based on miRNAs and have the potential to contribute to the development of targeted therapies and improved prognostic strategies of TNBC.
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MicroARNs , ARN Largo no Codificante , Neoplasias de la Mama Triple Negativas , Humanos , MicroARNs/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , ARN Largo no Codificante/genética , Pronóstico , ARN Mensajero/genética , Detección Precoz del Cáncer , Regulación Neoplásica de la Expresión Génica/genética , Biomarcadores de Tumor/genéticaRESUMEN
OBJECTIVES: Real-world experience regarding the effectiveness of co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (EVG/C/FTC/TAF) as a switch regimen is sparse among people living with HIV (PLWH) harbouring the M184V/I mutation with or without thymidine analogue-associated mutations (TAMs). METHODS: In this retrospective multicentre study, PLWH who were switched to EVG/C/FTC/TAF after having achieved viral suppression (plasma HIV RNA <200 copies/mL) for 6 months or longer were included. Patients with archived M184V/I mutation (case patients) were matched to controls without M184V/I mutation at a 1:4 ratio. Patients with a history of virological failure or resistance to elvitegravir were excluded. The primary endpoint was virological non-success (plasma HIV RNA ≥50 copies/mL) at Week 48 of switch using a modified FDA snapshot analysis. RESULTS: Overall, 100 case patients with the M184V/I mutation were identified, including 6 (6.0%) with K65R and 13 (13.0%) with at least one TAM, and were matched to 400 controls in terms of gender, age (mean = 40.3 versus 39.7 years) and cumulative exposure duration to tenofovir disoproxil fumarate (median = 146 versus 143 weeks). At Week 48, the rate of virological non-success for the case patients and controls was 5.0% (5/100) and 3.3% (13/400), respectively (difference = 1.7%; 95% CI = -2.9%-6.3%), while the rate of virological success was 88.0% and 89.5% for the case patients and controls, respectively. The presence of the K65R mutation or TAMs was not associated with virological non-response. CONCLUSIONS: Among virally suppressed PLWH, EVG/C/FTC/TAF is effective in maintaining viral suppression at Week 48 despite archived M184V/I mutation with or without TAMs.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adenina/análogos & derivados , Adulto , Alanina , Fármacos Anti-VIH/uso terapéutico , Cobicistat/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Mutación , Quinolonas , Estudios Retrospectivos , Tenofovir/análogos & derivadosRESUMEN
OBJECTIVE: To study the level of neuropsychological development in late preterm infants and early term infants at the age of 1 year. METHODS: A total of 1â257 children with a corrected age of 1 year were enrolled as subjects. According to gestational age at birth, they were divided into an early preterm group (28-33+6 weeks), a late preterm group (34-36+6 weeks), an early term group (37-38+6 weeks), and a full-term group (39-41+6 weeks). Gesell Developmental Schedules were used to assess the neuropsychological development of the children, and the groups were compared in terms of neuropsychological development at the age of 1 year. RESULTS: There were significant differences in the developmental quotients of the five functional areas (adaptability, gross motor, fine motor, language and social ability) between the four groups at the age of 1 year (P<0.05), and the full-term infants had the highest development quotients, followed by the early term infants, the late preterm infants, and the early preterm infants (P<0.05). The full-term infants had the lowest rate of developmental delay in each functional area, while the early preterm infants had the highest rate (P<0.05). Compared with the full-term infants, the early term infants had a higher risk of developmental delay in adaptability (OR=1.796, P<0.05), and the late preterm infants had a higher risk of developmental delay in adaptability (OR=2.651, P<0.05) and fine motor (OR=2.679, P<0.05), while the early preterm infants had a higher risk of developmental delay in adaptability (OR=4.069, P<0.05), fine motor (OR=3.710, P<0.05), and social ability (OR=3.515, P<0.05). CONCLUSIONS: The risk of neuropsychological developmental delay decreases with the increase in gestational age in children at the age of 1 year, with a dose-response effect. There are varying degrees of developmental delay in early term infants and late preterm infants, and health care follow-up for early term infants and late preterm infants should be taken seriously.
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Recien Nacido Prematuro , Nacimiento Prematuro , Desarrollo Infantil , Femenino , Estudios de Seguimiento , Edad Gestacional , Humanos , Lactante , Recién Nacido , EmbarazoRESUMEN
Clinical translation of therapeutic peptides, particularly those targeting intracellular protein-protein interactions (PPIs), has been hampered by their inefficacious cellular internalization in diseased tissue. Therapeutic peptides engineered into nanostructures with stable spatial architectures and smart disease targeting ability may provide a viable strategy to overcome the pharmaceutical obstacles of peptides. This study describes a strategy to assemble therapeutic peptides into a stable peptide-Au nanohybrid, followed by further self-assembling into higher-order nanoclusters with responsiveness to tumor microenvironment. As a proof of concept, an anticancer peptide termed ß-catenin/Bcl9 inhibitors is copolymerized with gold ion and assembled into a cluster of nanohybrids (pCluster). Through a battery of in vitro and in vivo tests, it is demonstrated that pClusters potently inhibit tumor growth and metastasis in several animal models through the impairment of the Wnt/ß-catenin pathway, while maintaining a highly favorable biosafety profile. In addition, it is also found that pClusters synergize with the PD1/PD-L1 checkpoint blockade immunotherapy. This new strategy of peptide delivery will likely have a broad impact on the development of peptide-derived therapeutic nanomedicine and reinvigorate efforts to discover peptide drugs that target intracellular PPIs in a great variety of human diseases, including cancer.
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Biosorption is an effective method for removing heavy metals from effluent. This work mainly aimed to evaluate the adsorption performance of the widely cultivated novel mushroom, Pleurotus eryngii, for the removal of Cu(II) from single aqueous solutions. Kinetics and equilibria were obtained using a batch technique. The sorption kinetics follows the pseudo-second-order model, whereas the adsorption equilibria are best described by the Langmuir model. The adsorption process is exothermic because both the Langmuir-estimated biosorption capacity and the heat of adsorption estimated from the Temkin model decreased with increasing tested temperature. Based on the adsorption intensity estimated by the Freundlich model and the mean adsorption free energy estimated by the Dubinin-Radushkevich model, the type of adsorption is defined as physical adsorption. The biomass of the macro-fungus P. eryngii has the potential to remove Cu(II) from a large-scale wastewater contaminated by heavy metals, because of its favorable adsorption, short biosorption equilibrium time of 20 min and remarkable biosorption capacity (15.19 mg g⻹ as calculated by the Langmuir model). The adsorbed metal-enriched mushroom is a high-quality bio-ore by the virtue of its high metal content of industrial mining grade and easy metal extractability.
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Cobre/metabolismo , Pleurotus/metabolismo , Contaminantes Químicos del Agua/metabolismo , Adsorción , Biodegradación Ambiental , Biomasa , Cobre/química , Cinética , Pleurotus/química , Pleurotus/crecimiento & desarrollo , Aguas Residuales/química , Contaminantes Químicos del Agua/químicaRESUMEN
AIM: To explore ocular surface manifestations of dry eye disease (DED) and its influencing factors in systemic lupus erythematosus (SLE) patients. METHODS: Ophthalmological examinations were conducted in SLE patients (n=43) and controls (n=41), including Ocular Surface Disease Index (OSDI), objective scatter index (OSI), tear meniscus height (TMH), lipid layer thickness (LLT), non-invasive Keratograph tear breakup time (NIKBUT), corneal fluorescein score (CFS), Schirmer I test. DED was diagnosed according to the Tear Film and Ocular Surface Society Dry Eye Workshop II Criteria. SLE patients were further divided into DED group and non-DED group, the disease activity, clinical manifestations and laboratory investigations were compared between the two groups. The disease activity was evaluated by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Receiver operative characteristic (ROC) curve and multiple-factor binary logistic regression were performed. RESULTS: SLE patients showed higher OSDI [9.1 (2.8-15.9) vs 6.3 (2.2-7.5), P=0.035], higher OSI [1.67 (1.09-2.60) vs 0.96 (0.87-1.60), P=0.001], higher CFS [1 (0-2) vs 0 (0-1), P=0.001], lower LLT [65 (42-100) vs 100 (79.5-100), P=0.010], and lower NIKBUT [8.03 (4.02-9.73) vs 9.67 (5.26-12.71), P=0.030] than controls. The 32.6% of SLE patients had DED, which was higher than 12.2% of healthy controls. DED group showed higher SLEDAI-2K score [9.7±6.1 vs 5.4±3.4, P=0.025], higher anti-cardiolipin antibody (ACL) [8.7 (3.5-13.2) vs 3.6 (2.0-6.9), P=0.035], and higher proportion of patients with cutaneous eruption [42.9% vs 6.9%, P=0.015] than non-DED group. According to multiple-factor binary logistic regression analysis, the SLEDAI-2K score (OR=1.194, P=0.041) and cutaneous eruption (OR=7.094, P=0.045) could be consider as risk factors for DED in SLE patients. The ROC curve of the combined factors including age, disease duration, SLEDAI-2K score, ACL, and cutaneous eruption was analyzed, with a sensitivity of 0.786, a specificity of 0.793, and an area under curve of 0.820. CONCLUSION: Ocular surface affection is frequent in SLE patients, and patients with high disease activity and cutaneous eruption show increased risk of DED.
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The gut microbiome plays a significant role in methamphetamine addiction. Previous studies using short-read amplicon sequencing have described alterations in microbiota at the genus level and predicted function, in which taxonomic resolution is insufficient for accurate functional measurements. To address this limitation, we employed metagenome sequencing to intuitively associate species to functions of gut microbiota in methamphetamine-induced conditioned place preference. We observed differential perturbations of species-level functional profiling of the gut microbiota across phases of METH-induced CPP, with alterations in SCFA metabolism and bacterial motility at the acquisition phase and substance dependence-alcoholism pathway and amino acid metabolism at the extinction phase. Our findings suggest that reduced beneficial bacteria, i.e., Lactobacillus reuteri, contributed to the alteration of SCFA metabolism, while the increased abundance of Akkermansia muciniphila during the extinction phase may be associated with altered phenylalanine, tyrosine, and tryptophan metabolism and substance dependence pathway. Our study further supports the association between specific microbial taxa and METH-induced rewarding.
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Estimulantes del Sistema Nervioso Central , Microbioma Gastrointestinal , Metanfetamina , Metanfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Clásico , RecompensaRESUMEN
BACKGROUND: Breast cancer (BC) stands as the most prevalent malignancy among women and ranks as the second most frequently diagnosed cancer globally among newly identified cases. Post-GPI attachment to proteins factor 3ï¼PGAP3ï¼was reported to involve in lipid remodeling. However, its specific role in breast cancer remains inadequately elucidated. Consequently, the principal objective of this study was to investigate the clinical significance of PGAP3 in breast cancer. METHODS: We conducted an extensive analysis using both public databases and our own sample cohort to assess the role of PGAP3 in breast cancer. Immunohistochemistry was employed to assess PGAP3 expression, immune markers, and the co-expression of PGAP3 with key susceptibility genes. Data analysis was performed using the R programming language. RESULTS: Our findings revealed that PGAP3 is significantly overexpressed in breast cancer, particularly in human epidermal growth factor 2 positive (HER2 +) breast cancer cases (p < 0.001). Co-expression analyses demonstrated a significant correlation between PGAP3 and susceptibility genes associated with breast cancer, including BRCA1, BRCA2, PALB2, ATM, CHEK2, RAD51C, and RAD51D (p < 0.05). Logistic regression analysis identified PGAP3 as a significant predictor of estrogen receptor (ER), progesterone receptor (PR), HER2, and lymph node metastasis status (p < 0.01). Furthermore, higher PGAP3 expression was associated with decreased infiltration of CD8 + T cells in breast cancer samples. CONCLUSION: Our study sheds light on the clinical significance of PGAP3 in breast cancer. PGAP3 is not only overexpressed in breast cancer but also correlates with key susceptibility genes, lymph node metastasis, and CD8 + T cell infiltration. These findings provide valuable insights into the potential role of PGAP3 as a biomarker in breast cancer and may contribute to our understanding of the disease's pathogenesis.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Metástasis Linfática , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Linfocitos T CD8-positivos , Receptores de Progesterona , Biomarcadores de Tumor/metabolismo , Hidrolasas de Éster Carboxílico , Receptores de Superficie CelularRESUMEN
Background: Thyrotropin receptor (TSHR) plays a central role in maintaining thyroid function and TSHR impairment causes hypothyroidism, which is often associated with metabolic disarrangement. The most common type of hypothyroidism is autoimmune disease-related and the mechanism, particularly with respect to the role of microRNAs (miRNAs), has not been delineated. Methods: Serum from 30 patients with subclinical hypothyroidism (SCH) and 30 healthy individuals were collected and exosomal miR-146a (exo-miR-146a) was examined, followed by extensive mechanistic investigation using various molecular and cellular experimental approaches and genetic-knockout mouse models. Results: Our clinical investigation showed that exo-miR-146a was systemically elevated in the serum of patients with SCH (p = 0.04) compared with healthy individuals, prompting us to investigate the biological effects of miR-146a in cells. We found that miR-146a could target and down-regulate neuron-glial antigen 2 (Ng2), with consequent down-regulation of TSHR. We next generated a thyroid-specific Ng2 knockout (Thy-Ng2-/-) mouse model and found a significant down-regulation of TSHR in Thy-Ng2-/- mice, accompanied by the development of hypothyroidism and metabolic disorders. We further found that a decrease in NG2 resulted in decreased receptor tyrosine kinase-linked downstream signaling and down-regulation of c-Myc, consequently resulting in up-regulation of miR-142 and miR-146a in thyroid cells. Up-regulated miR-142 targeted the 3'-untranslated region (UTR) of TSHR messenger RNA (mRNA) and post-transcriptionally down-regulated TSHR, explaining the development of hypothyroidism above. Local up-regulation of miR-146a in thyroid cells augments the earlier cited processes initiated by systemically elevated miR-146a, thereby forming a feedback loop to propel the development and progression of hypothyroidism. Conclusions: This study has uncovered a self-augmenting molecular loop initiated by elevated exo-miR-146a to suppress TSHR through targeting and down-regulating NG2, thereby initiating and propelling the development and progression of hypothyroidism.
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Hipotiroidismo , MicroARNs , Animales , Ratones , Retroalimentación , Hipotiroidismo/genética , MicroARNs/genética , MicroARNs/metabolismo , Receptores de Tirotropina/genéticaRESUMEN
OBJECTIVE: To compare the postoperative recovery of primary pterygium excision combined with either limbal stem cell transplantation (LSCT) or amniotic membrane transplantation (AMT). METHODS: All relevant studies on the primary pterygium excision combined with either LSCT or AMT conducted before August 2022 were extracted from PubMed, EMBASE, Web of Science, and Cochrane Library databases. The main outcomes compared were tear film stability at 1, 3, and 6 months after surgery, postoperative corneal epithelial healing time, recurrence rate, and complications. RESULTS: Sixteen randomized controlled trials (RCTs) with 1390 eye cases were included in this meta-analysis. We found that patients of the AMT group improved significantly in the results of the tear break-up time (BUT) and Schirmer I test at 1 month after surgery (BUT: MD=-0.37, 95% CI: -0.62, -0.12, P<0.05; Schirmer I test: MD=-0.32, 95% CI: -0.57, -0.07, P<0.05) compared with those of the LSCT group, suggesting that the early stage of tear film stability after primary pterygium excision combined with AMT was superior to the LSCT combination. However, according to the Schirmer I test result, the patients in the LSCT group showed increased tear production compared to the AMT group at 3 and 6 months after surgery (3 months: MD=0.36, 95% CI: 0.08, 0.64, P<0.05; 6 months: MD=0.33, 95% CI: 0.07, 0.60, P<0.05), suggesting that the LSCT combination was superior to the AMT combination in long-term postoperative tear film stability. As for postoperative corneal epithelial healing time, the LSCT group exhibited shorter time than the AMT group (MD=-1.17, 95% CI: -2.15, -0.19, P<0.05). Furthermore, the recurrence rate was lower in the LSCT group than in the AMT group (RR=0.42, 95% CI: 0.30, 0.59, P<0.05). Lastly, there was no statistical difference in BUT and complication rate at 3 and 6 months after surgery between the LSCT and AMT groups. CONCLUSIONS: Our analysis suggests that primary pterygium excision combined with LSCT may be a better choice compared to the combination with AMT in postoperative recovery.
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PURPOSE: Sorafenib has been reported to reduce blood glucose levels in diabetic and non-diabetic patients in previous retrospective studies. However, the mechanism of which the hypoglycemic effects of sorafenib is not clearly explored. In this study, we investigated the effect of sorafenib on blood glucose levels in diabetic and normal mice and explored the possible mechanism. METHODS: We established a mouse model of type 2 diabetes by a high-fat diet combined with a low-dose of streptozotocin (STZ), to identify the hypoglycemic effect of sorafenib in different mice. Glucose tolerance, insulin tolerance and pyruvate tolerance tests were done after daily gavage with sorafenib to diabetic and control mice. To explore the molecular mechanism by which sorafenib regulates blood glucose levels, hepatic glucose metabolism signaling was studied by a series of in vivo and in vitro experiments. RESULTS: Sorafenib reduced blood glucose levels in both control and diabetic mice, particularly in the latter. The diabetic mice exhibited improved glucose and insulin tolerance after sorafenib treatment. Further studies showed that the expressions of gluconeogenesis-related enzymes, such as PCK1, G6PC and PCB, were significantly decreased upon sorafenib treatment. Mechanistically, sorafenib downregulates the expression of c-MYC downstream targets PCK1, G6PC and PCB through blocking the ERK/c-MYC signaling pathway, thereby playing its hypoglycemic effect by impairing hepatic glucose metabolism. CONCLUSION: Sorafenib reduces blood glucose levels through downregulating gluconeogenic genes, especially in diabetic mice, suggesting the patients with T2DM when treated with sorafenib need more emphasis in monitoring blood glucose to avoid unnecessary hypoglycemia.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Insulinas , Ratones , Animales , Glucemia/metabolismo , Glucosa/metabolismo , Sorafenib/farmacología , Sorafenib/uso terapéutico , Diabetes Mellitus Experimental/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/farmacología , Proteínas Proto-Oncogénicas c-myc/uso terapéutico , Transducción de Señal , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hígado/metabolismo , Insulinas/metabolismo , Insulinas/farmacología , Insulinas/uso terapéutico , Insulina/metabolismoRESUMEN
AIM: To investigate the effects of on ocular surface microbiota in patients who received intravitreal injections. METHODS: Samples of ocular surface microbiota were obtained from 41 eyes of 41 patients who visited the Department of Ophthalmology. Patients were separated for three groups. Group A did not receive perioperative managements or intravitreal injection. Group B1 received only once and B2 received more than twice. In operating room, the samples were collected on the ocular surface. Operating taxonomic units (OTUs) clustering and alpha/beta diversity analysis was performed. The microbial 16S rRNA from samples were analyzed using the HiSeq 2500 platform. RESULTS: Alpha diversity did not differ in each group, and beta diversity differed in the B2 group. Beta diversity showed a significant difference between Group A and B2 (P=0.048). With the perioperative managements before intravitreal injection, the composition and relative abundance were altered. Top 10 microbiota on phylum and genus level, and then microbiota notably changed at genus level were listed. Gram-negative bacteria were varied more. Furthermore, Proteus was not found in Groups A and B1, but it was appeared after the patients received perioperative management and intravitreal injections in Group B2. CONCLUSION: With the perioperative managements, the balance of microbiota on the ocular surface is destroyed, and relative composition and abundance of microbiota on the ocular surface is obviously altered. The clinical doctors should pay more attention on the consequence of perioperative managements before intravitreal injection.
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BACKGROUND: Cancer/testis antigen (CTA) is a class of antigen molecules mainly expressed in the germinal epithelium of testis and some tumor tissues. FBXO39, also known as F-box protein 39, is a crucial CTA molecule. F-box protein 39 (FBXO39) is overexpressed in cervical squamous cell carcinomas (CESCs), however its function in cancer development and clinical significance are still unknown. METHODS: We used paraffin-embedded tumor tissues from 124 patients and fresh-harvested and paired adjacent normal esophageal tissues from 15 CESC patients who underwent primary surgical resection in Xijing Hospital between 2015 and 2020. The expression level of FBXO39 was evaluated through immunohistochemistry, Western Blot and q-PCR. Prognostic and survival analyses were conducted using univariate/multivariate analysis and log-rank analysis with SPSS 23.0. CCK-8, wound-healing and Transwell assays were applied to demonstrate that FBXO39 promoted the proliferation, migration and invasion. Finally, we constructed a xenografts model of the C-33A cell lines to observe the effect of FBXO39 on tumorigenesis in vivo. RESULTS: Immunohistochemical results showed that FBXO39 was highly expressed in cancer tissues than in corresponding non-cancer tissues. Similarly, we proved this result at protein and mRNA level by Western-Blotting and q-PCR. Prognostic and OS analyses showed that the FBXO39 expression level was an individual prognostic factor in CESC patients. CCK-8, wound-healing and Transwell assays proved that the overexpression of FBXO39 in Si-Ha cells promoted the proliferation, migration and invasion of the cells. Knocking down FBXO39 in C-33A cells inhibited the proliferation, migration and invasion of cells. The experimental results of xenografts model in nude mice showed that the knockdown of FBXO39 in C-33A cells slowed down the growth of tumor. CONCLUSION: FBXO39 is a poor prognostic factor of cervical squamous cell carcinoma, which may provide a novel therapeutic target for CESC.
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Real-world experience with low-level viraemia (LLV) and its impact remain less reported among people living with HIV (PLWH) who receive antiretroviral therapy (ART) containing second-generation integrase strand transferase inhibitors, including dolutegravir and bictegravir. This retrospective cohort study included virally suppressed PLWH who achieved plasma HIV-RNA viral load (PVL) <50 copies/mL for ≥6 months and were switched to either dolutegravir- or bictegravir-based ART. Incidence rates of developing LLV events (PVL, 50-200 copies/mL) and virologic failure (VF) (PVL ≥1000 copies/mL) were compared between the dolutegravir and bictegravir cohorts. A total of 623 and 862 PLWH switched to dolutegravir-based and bictegravir-based ART, respectively, were included. The incidence rate of developing LLV was 6.2 per 100 person-years of follow-up (PYFU) in the bictegravir cohort and 3.8 per 100 PYFU in the dolutegravir cohort [incidence rate ratio (IRR) = 1.63, 95% confidence interval (CI), 0.90-2.95; P = 0.08], while rates of VF were 0.69 per 100 PYFU and 0.95 per 100 PYFU, respectively, in the bictegravir and dolutegravir cohorts (IRR = 0.72, 95% CI 0.12-3.39; P = 0.34). Presence of LLV events was not associated with subsequent VF in multivariate analysis. Secondary analysis also demonstrated that resistance-associated mutations (RAMs) to nucleoside reverse transcriptase inhibitors (NRTIs) before switch were not associated with adverse virologic outcomes in either cohort. In conclusion, among virally suppressed PLWH, the incidences of developing LLV or VF were similar after switch to dolutegravir- or bictegravir-based ART. Pre-existing RAMs to NRTIs or LLV events were not associated with subsequent VF.
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Fármacos Anti-VIH , Infecciones por VIH , Adenina/uso terapéutico , Alanina , Amidas , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Oxazinas/uso terapéutico , Piperazinas , Piridonas/uso terapéutico , Estudios Retrospectivos , Tenofovir/análogos & derivados , Tenofovir/uso terapéutico , Carga Viral , Viremia/tratamiento farmacológicoRESUMEN
BACKGROUND: Diagnosis of congenital syphilis (CS) is not straightforward and can be challenging. This study aimed to evaluate the validity of an algorithm using timing of maternal antisyphilis treatment and titres of non-treponemal antibody as predictors of CS. METHODS: Confirmed CS cases and those where CS was excluded were obtained from the Guangzhou Prevention of Mother-to-Child Transmission of syphilis programme between 2011 and 2019. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) using receiver operating characteristics (ROC) in two situations: (1) receiving antisyphilis treatment or no-treatment during pregnancy and (2) initiating treatment before 28 gestational weeks (GWs), initiating after 28 GWs or receiving no treatment for syphilis seropositive women. RESULTS: Among 1558 syphilis-exposed children, 39 had confirmed CS. Area under the curve, sensitivity and specificity of maternal non-treponemal titres before treatment and treatment during pregnancy were 0.80, 76.9%, 78.7% and 0.79, 69.2%, 88.7%, respectively, for children with CS. For the algorithm, ROC results showed that PPV and NPV for predicting CS were 37.3% and 96.4% (non-treponemal titres cut-off value 1:8 and no antisyphilis treatment), 9.4% and 100% (non-treponemal titres cut-off value 1:16 and treatment after 28 GWs), 4.2% and 99.5% (non-treponemal titres cut-off value 1:32 and treatment before 28 GWs), respectively. CONCLUSIONS: An algorithm using maternal non-treponemal titres and timing of treatment during pregnancy could be an effective strategy to diagnose or rule out CS, especially when the rate of loss to follow-up is high or there are no straightforward diagnostic tools.
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Tamizaje Masivo/métodos , Complicaciones Infecciosas del Embarazo/inmunología , Sífilis Congénita/diagnóstico , Sífilis Congénita/inmunología , Adulto , Algoritmos , China/epidemiología , Femenino , Edad Gestacional , Humanos , Incidencia , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Valor Predictivo de las Pruebas , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/prevención & control , Estudios Retrospectivos , Factores de Riesgo , Sensibilidad y Especificidad , Serodiagnóstico de la Sífilis/métodos , Sífilis Congénita/tratamiento farmacológico , Sífilis Congénita/epidemiología , Treponema pallidum/inmunologíaRESUMEN
BACKGROUND: To eliminate mother-to-child transmission of syphilis, the Chinese government recommends a treatment regimen that slightly differs from the World Health Organization- (WHO-) recommended treatment. However, little is known about their difference in efficacy. This study is aimed at comparing the effect of China-recommended and WHO-recommend treatment regimens on adverse pregnancy outcomes (APOs) and at examining associated risk factors of APOs among syphilis-seropositive women. METHODS: Using the syphilis registry data, we retrospectively collected data from 4488 syphilis-infected pregnant women in Guangzhou during 2011-2018. Multivariate analyses were used to investigate the association between treatment regimens and APOs (ectopic pregnancy, spontaneous abortion, stillbirth, preterm birth or low birth weight, newborn smaller than gestational age, congenital syphilis, and infant death) and the association between risk factors and APOs. RESULTS: Of 3474 participants, 27.3% had at least one APO. Compared to those receiving WHO-recommended treatment, women who received China-recommended treatment were less likely to have APOs (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.38-0.57), whereas those who received no treatment had 1.6 times higher odds of experiencing APOs. One common risk factor across different APOs was high levels of log2-transformed toluidine red unheated serum test (TRUST) titers before treatment (OR 1.14, 95% CI 1.10-1.19). China-recommended treatment was effective in reducing APOs for those with TRUST ≥ 1 : 8 (OR 0.21, 95% CI 0.14-0.29) and those with TRUST < 1 : 8 (OR 0.62, 95% CI 0.50-0.77). CONCLUSIONS: Syphilis-seropositive women receiving China-recommended treatment had lower odds of APOs, especially when TRUST titers before treatment were high. Findings can be used to guide health professionals to reduce APOs among syphilis-infected mothers and promote nationwide use of China-recommended treatment.