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Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.
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Tecido Adiposo Branco , Diferenciação Celular , Endotelina-3 , Receptor de Endotelina B , Transdução de Sinais , Termogênese , Animais , Tecido Adiposo Branco/metabolismo , Termogênese/genética , Humanos , Camundongos , Receptor de Endotelina B/metabolismo , Receptor de Endotelina B/genética , Endotelina-3/metabolismo , Endotelina-3/genética , Masculino , Obesidade/metabolismo , Obesidade/genética , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica , Resistência à Insulina , Adipócitos Brancos/metabolismo , Camundongos Knockout , Adipócitos Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Intolerância à Glucose/metabolismo , Temperatura BaixaRESUMO
Chrysanthemum morifolium Ramat. (C. morifolium), as a traditional ornamental plant, it has multiple values, including edible, economic, nutritional and even medicinal values, which is used as herbal medicine and a new food resource in the world. Polysaccharides are one of the main bioactive components in C. morifolium, which have various health benefits such as improving functional constipation, improving colitis, anti-glycosylation, antioxidant, anti-angiogenesis, immunomodulation, prebiotic, and α-glucosidase inhibitory activities. This paper describes the extraction, purification, structural characteristics, health benefits, structural-activity relationships, applications, and analyses the shortcomings of the major relevant studies exist on C. morifolium polysaccharides. In addition, the potential mechanisms of the health benefits of C. morifolium polysaccharides were summarized. This study can provide reference and direction for further research and development of C. morifolium polysaccharides.
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Background: The tertiary lymphatic structure (TLS) is an important component of the tumor immune microenvironment and has important significance in patient prognosis and response to immune therapy. However, the underlying mechanism of TLS in soft tissue sarcoma remains unclear. Methods: A total of 256 RNAseq and 7 single-cell sequencing samples were collected from TCGA-SARC and GSE212527 cohorts. Based on published TLS-related gene sets, four TLS scores were established by GSVA algorithm. The immune cell infiltration was calculated via TIMER2.0 and "MCPcounter" algorithms. In addition, the univariate, LASSO, and multivariate-Cox analyses were used to select TLS-related and prognosis-significant hub genes. Single-cell sequencing dataset, clinical immunohistochemical, and cell experiments were utilized to validate the hub genes. Results: In this study, four TLS-related scores were identified, and the total-gene TLS score more accurately reflected the infiltration level of TLS in STS. We further established two hub genes (DUSP9 and TNFSF14) prognosis markers and risk scores associated with soft tissue sarcoma prognosis and immune therapy response. Flow cytometry analysis showed that the amount of CD3, CD8, CD19, and CD11c positive immune cell infiltration in the tumor tissue dedifferentiated liposarcoma patients was significantly higher than that of liposarcoma patients. Cytological experiments showed that soft tissue sarcoma cell lines overexpressing TNFSF14 could inhibit the proliferation and migration of sarcoma cells. Conclusion: This study systematically explored the TLS and related genes from the perspectives of bioinformatics, clinical features and cytology experiments. The total-gene TLS score, risk score and TNFSF14 hub gene may be useful biomarkers for predicting the prognosis and immunotherapy efficacy of soft tissue sarcoma.
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Biomarcadores Tumorais , Imunoterapia , Sarcoma , Microambiente Tumoral , Humanos , Sarcoma/genética , Sarcoma/terapia , Sarcoma/imunologia , Sarcoma/diagnóstico , Biomarcadores Tumorais/genética , Prognóstico , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Regulação Neoplásica da Expressão Gênica , Feminino , Masculino , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Perfilação da Expressão Gênica , Análise de Célula ÚnicaRESUMO
Although exogenous calcitonin generelated peptide (CGRP) protects against hyperoxiainduced lung injury (HILI), the underlying mechanisms remain unclear. The present study attempted to elucidate the molecular mechanism by which CGRP protects against hyperoxiainduced alveolar cell injury. Human alveolar A549 cells were treated with 95% hyperoxia to establish a hyperoxic cell injury model. ELISA was performed to detect the CGRP secretion. Immunofluorescence, quantitative (q)PCR, and western blotting were used to detect the expression and localization of CGRP receptor (CGRPR) and transient receptor potential vanilloid 1 (TRPV1). Cell counting kit8 and flow cytometry were used to examine the proliferation and apoptosis of treated cells. Digital calcium imaging and patch clamp were used to analyze the changes in intracellular Ca2+ signaling and membrane currents induced by CGRP in A549 cells. The mRNA and protein expression levels of Cyclin D1, proliferating cell nuclear antigen (PCNA), Bcl2 and Bax were detected by qPCR and western blotting. The expression levels of CGRPR and TRPV1 in A549 cells were significantly downregulated by hyperoxic treatment, but there was no significant difference in CGRP release between cells cultured under normal air and hyperoxic conditions. CGRP promoted cell proliferation and inhibited apoptosis in hyperoxia, but selective inhibitors of CGRPR and TRPV1 channels could effectively attenuate these effects; TRPV1 knockdown also attenuated this effect. CGRP induced Ca2+ entry via the TRPV1 channels and enhanced the membrane nonselective currents through TRPV1 channels. The CGRPinduced increase in intracellular Ca2+ was reduced by inhibiting the phospholipase C (PLC)/protein kinase C (PKC) pathway. Moreover, PLC and PKC inhibitors attenuated the effects of CGRP in promoting cell proliferation and inhibiting apoptosis. In conclusion, exogenous CGRP acted by inversely regulating the function of TRPV1 channels in alveolar cells. Importantly, CGRP protected alveolar cells from hyperoxiainduced injury via the CGRPR/TRPV1/Ca2+ axis, which may be a potential target for the prevention and treatment of the HILI.
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Células Epiteliais Alveolares , Peptídeo Relacionado com Gene de Calcitonina , Hiperóxia , Lesão Pulmonar , Humanos , Células A549 , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Apoptose/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hiperóxia/metabolismo , Hiperóxia/patologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologiaRESUMO
The genus Lilium (Lilium) has been widely used in East Asia for over 2000 years due to its rich nutritional and medicinal value, serving as both food and medicinal ingredient. Polysaccharides, as one of the most important bioactive components in Lilium, offer various health benefits. Recently, polysaccharides from Lilium plants have garnered significant attention from researchers due to their diverse biological properties including immunomodulatory, anti-oxidant, anti-diabetic, anti-tumor, anti-bacterial, anti-aging and anti-radiation effects. However, the limited comprehensive understanding of polysaccharides from Lilium plants has hindered their development and utilization. This review focuses on the extraction, purification, structural characteristics, biological activities, structure-activity relationships, applications, and relevant bibliometrics of polysaccharides from Lilium plants. Additionally, it delves into the potential development and future research directions. The aim of this article is to provide a comprehensive understanding of polysaccharides from Lilium plants and to serve as a basis for further research and development as therapeutic agents and multifunctional biomaterials.
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Lilium , Polissacarídeos , Lilium/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/isolamento & purificação , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Relação Estrutura-Atividade , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/isolamento & purificaçãoRESUMO
Background: The demand for genital plastic surgery has increased dramatically among female patients globally. Although various labia minora reduction procedures have been applied with different indications, advantages, and disadvantages, none has been universally accepted as the best method. So, we presented an innovative strategy for this increasingly demanded reconstructive procedure. Methods: In this retrospective study, we included 29 patients seen between November 2020 and May 2023 with hypertrophic labia minora. The patients with hypertrophic labia minora after serrated-shaped resection were included for analysis. Patient satisfaction and complications were evaluated through the follow-up after the operation. Results: Patients with a mean age of 27.1 years (range 19-47 y) performed labia minora reduction via serrated-shaped resection. One patient experienced incision dehiscence, requiring additional surgical revision. One patient experienced postoperative cosmetic asymmetry and also performed secondary repair surgery. One patient experienced urinary retention, which was relieved after urinary catheterization. High overall patient satisfaction has been achieved after a median follow-up of 6.7 months (range 1-24 months). No flap necrosis, sexual dysfunction, or hypertrophic scarring has been reported. Conclusions: Results suggested that serrated-shaped resection is a novel technique for repairing hypertrophic labia minora with high efficiency and satisfaction. The procedure could effectively improve the appearance of the labia minora and reduce complications.
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ETHNOPHARMACOLOGICAL RELEVANCE: Dichroa febrifuga Lour., a toxic but extensively used traditional Chinese medicine with a remarkable effect, is commonly called "Changshan" in China. It has been used to treat malaria and many other parasitic diseases. AIM OF THE REVIEW: The study aims to provide a current overview of the progress in the research on traditional use, phytochemistry, pharmacological activities, toxicology, and methods of toxicity reduction of D. febrifuga. Additionally, further research directions and development prospects for the plant were put forward. MATERIALS AND METHODS: The article uses "Dichroa febrifuga Lour." "D. febrifuga" as the keyword and all relevant information on D. febrifuga was collected from electronic searches (Elsevier, PubMed, ACS, CNKI, Google Scholar, and Baidu Scholar), doctoral and master's dissertations and classic books about Chinese herbs. RESULTS: 30 chemical compounds, including alkaloids, terpenoids, flavonoids and other kinds, were isolated and identified from D. febrifuga. Modern pharmacological studies have shown that these components have a variety of pharmacological activities, including anti-malarial activities, anti-inflammatory activities, anti-tumor activities, anti-parasitic activities and anti-oomycete activities. Meanwhile, alkaloids, as the material basis of its efficacy, are also the source of its toxicity. It can cause multiple organ damage, including liver, kidney and heart, and cause adverse reactions such as nausea and vomiting, abdominal pain and diarrhea. In the current study, the toxicity can be reduced by modifying the structure of the compound, processing and changing the dosage forms. CONCLUSIONS: There are few studies on the chemical constituents of D. febrifuga, so the components and their structure characterization contained in it can become the focus of future research. In view of the toxicity of D. febrifuga, there are many methods to reduce it, but the safety and rationality of these methods need further study.
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Etnofarmacologia , Medicina Tradicional Chinesa , Compostos Fitoquímicos , Humanos , Animais , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/toxicidade , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , FitoterapiaRESUMO
The Janus kinase/signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway controls multiple biological processes, including cell survival, proliferation, and differentiation. Abnormally activated STAT3 signaling promotes tumor cell growth, proliferation, and survival, as well as tumor invasion, angiogenesis, and immunosuppression. Hence, JAK/STAT3 signaling has been considered a promising target for antitumor therapy. In this study, a number of ageladine A derivative compounds were synthesized. The most effective of these was found to be compound 25. Our results indicated that compound 25 had the greatest inhibitory effect on the STAT3 luciferase gene reporter. Molecular docking results showed that compound 25 could dock into the STAT3 SH2 structural domain. Western blot assays demonstrated that compound 25 selectively inhibited the phosphorylation of STAT3 on the Tyr705 residue, thereby reducing STAT3 downstream gene expression without affecting the expression of the upstream proteins, p-STAT1 and p-STAT5. Compound 25 also suppressed the proliferation and migration of A549 and DU145 cells. Finally, in vivo research revealed that 10 mg/kg of compound 25 effectively inhibited the growth of A549 xenograft tumors with persistent STAT3 activation without causing significant weight loss. These results clearly indicate that compound 25 could be a potential antitumor agent by inhibiting STAT3 activation.
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Janus Quinases , Transdução de Sinais , Humanos , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Janus Quinases/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo , Proliferação de Células , Ensaios Antitumorais Modelo de Xenoenxerto , ApoptoseRESUMO
Cuproptosis is a newly discovered programmed cell death process, and several cuproptosis-related genes have been reported to regulate cancer cell proliferation and progression. The association between cuproptosis and tumor microenvironment in gastric cancer (GC) remains unclear. This study aimed to explore multiomics characteristics of cuproptosis-related genes regulating tumor microenvironment and provide strategies for prognosis and prediction of immunotherapy response in GC patients. We collected 1401 GC patients from the TCGA and 5 GEO data sets and identified three different cuproptosis-mediated patterns, each of which shared a distinct tumor microenvironment and different overall survival. The GC patients with high cuproptosis levels were enriched in CD8+ T cells and had a better prognosis. Whereas, the low cuproptosis level patients were associated with inhibitory immune cell infiltration and had the worst prognosis. In addition, we constructed a 3-gene (AHCYL2, ANKRD6 and FDGFRB) cuproptosis-related prognosis signature (CuPS) via Lasso-Cox and multivariate Cox regression analysis. The GC patients in the low-CuPS subgroup had higher TMB levels, MSI-H fractions, and PD-L1 expression, which suggests a better immunotherapy response. Therefore, the CuPS might have the potential value for predicting prognosis and immunotherapy sensitivity in GC patients.
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Background: Gastric cancer (GC) is an aggressive malignant tumor with a high degree of heterogeneity, and its immune microenvironment is closely associated with tumor growth, development and drug resistance. Therefore, a classification system of gastric cancer based explicitly on the immune microenvironment context might enrich the strategy for gastric cancer prognosis and therapy. Methods: A total of 668 GC patients were collected from TCGA-STAD (n = 350), GSE15459 (n = 192), GSE57303 (n = 70) and GSE34942 (n = 56) datasets. Three immune-related subtypes (immunity-H, -M, and -L) were identified by hierarchical cluster analysis based on the ssGSEA score of 29 immune microenvironment-related gene sets. The immune microenvironment-related prognosis signature (IMPS) was constructed via univariate Cox regression, Lasso-Cox regression and multivariate Cox regression, and nomogram model combining IMPS and clinical variables was further constructed by the "rms" package. RT-PCR was applied to validate the expression of 7 IMPS genes between two human GC cell lines (AGS and MKN45) and one normal gastric epithelial cell line (GES-1). Results: The patients classified as immunity-H subtype exhibited highly expressed immune checkpoint and HLA-related genes, with enriched naïve B cells, M1 macrophages and CD8 T cells. We further constructed and validated a 7-gene (CTLA4, CLDN6, EMB, GPR15, ENTPD2, VWF and AKR1B1) prognosis signature, termed as IMPS. The patients with higher IMPS expression were more likely to be associated with higher pathology grade, more advanced TNM stages, higher T and N stage, and higher ratio of death. In addition, the prediction values of the combined nomogram in predicting 1-year (AUC = 0.750), 3-year (AUC = 0.764) and 5-year (AUC = 0.802) OS was higher than IMPS and individual clinical characteristics. Conclusions: The IMPS is a novel prognosis signature associated with the immune microenvironment and clinical characteristics. The IMPS and the combined nomogram model provide a relatively reliable predictive index for predicting the survival outcomes of gastric cancer.
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The JAK/STAT3 signaling pathway is aberrantly hyperactivated in many cancers, promoting cell proliferation, survival, invasiveness, and metastasis. Thus, inhibitors targeting JAK/STAT3 have enormous potential for cancer treatment. Herein, we modified aldisine derivatives by introducing the isothiouronium group, which can improve the antitumor activity of the compounds. We performed a high-throughput screen of 3157 compounds and identified compounds 11a, 11b, and 11c, which contain a pyrrole [2,3-c] azepine structure linked to an isothiouronium group through different lengths of carbon alkyl chains and significantly inhibited JAK/STAT3 activities. Further results showed that compound 11c exhibited the optimal antiproliferative activity and was a pan-JAKs inhibitor capable of inhibiting constitutive and IL-6-induced STAT3 activation. In addition, compound 11c influenced STAT3 downstream gene expression (Bcl-xl, C-Myc, and Cyclin D1) and induced the apoptosis of A549 and DU145 cells in a dose-dependent manner. The antitumor effects of 11c were further demonstrated in an in vivo subcutaneous tumor xenograft experiment with DU145 cells. Taken together, we designed and synthesized a novel small molecule JAKs inhibitor targeting the JAK/STAT3 signaling pathway, which has predicted therapeutic potential for JAK/STAT3 overactivated cancer treatment.
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Isotiurônio , Transdução de Sinais , Humanos , Isotiurônio/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Apoptose , Azepinas/farmacologia , Pirróis/farmacologia , Fator de Transcrição STAT3/metabolismoRESUMO
BACKGROUND: Double aortic arch is the most common form of complete vascular ring. The trachea and/or esophagus could be compressed by the complete vascular ring, which may lead to early respiratory and/or esophageal symptoms in children with double aortic arch. Accurate prenatal assessment of tracheal compression could provide relevant information for perinatal clinical management of double aortic arch and emergency treatment of infants with double aortic arch. The fetal trachea is filled with amniotic fluid and can be clearly visualized with prenatal ultrasound. Previous studies reported the use of prenatal ultrasound to measure the tracheal internal diameters in normal fetuses and showed a linear correlation between the fetal tracheal internal diameters and gestational age. However, to the best of our knowledge, few studies have quantitatively evaluated tracheal compression in fetuses with double aortic arch using ultrasound. OBJECTIVE: This study aimed to evaluate the tracheal compression caused by the vascular ring in fetuses with double aortic arch using prenatal ultrasound and to analyze the relationship between tracheal compression and postnatal clinical symptoms. STUDY DESIGN: The data of fetuses with double aortic arch diagnosed with prenatal ultrasound at 2 institutions from January 2011 to April 2021 were retrospectively analyzed. Singleton pregnancies with normal fetuses as the control group were prospectively recruited. The tracheal compression-evaluated by comparing the tracheal internal diameter z scores against the gestational age-was assessed in fetuses with double aortic arch and in normal fetuses. The live-born infants with double aortic arch were divided into symptomatic and asymptomatic groups for the comparison of z scores. The receiver operating characteristic curve for the tracheal internal diameter z score cutoffs and prediction of symptomatic infants with double aortic arch was plotted. Intraobserver and interobserver agreements were investigated. RESULTS: A total of 26 fetuses with double aortic arch were diagnosed, and 14 fetuses (53.8%) with double aortic arch were delivered alive. Among the 14 live-born infants, 7 (50.0%) were symptomatic, whereas 7 (50.0%) were asymptomatic. The tracheal internal diameter z scores were significantly lower in the double aortic arch group than in the normal groups (-0.62±1.36 vs 0.00±0.78; P<.001). The tracheal internal diameter z scores were significantly lower in the symptomatic group than in the asymptomatic group (-1.42±0.92 vs -0.49±0.96; P=.018). The area under the curve was 0.878 (95% confidence interval, 0.689-1.000). Using a tracheal internal diameter z scores cutoff of -1.21, the sensitivity was 71%, and the specificity was close to 100%. The intraclass correlation coefficients of interobserver and intraobserver agreements were 0.987 (95% confidence interval, 0.980-0.992) and 0.975 (95% confidence interval, 0.955-0.987), respectively. CONCLUSION: The clinical symptoms in infants with double aortic arch were associated with prenatal tracheal compression, which can be prenatally evaluated using ultrasound. If fetuses are diagnosed with double aortic arch, prenatal surveillance of the tracheal internal diameters and comparison with z score reference ranges could provide pertinent information that would aid perinatal clinical management.
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Anel Vascular , Lactente , Criança , Feminino , Humanos , Gravidez , Anel Vascular/diagnóstico por imagem , Anel Vascular/epidemiologia , Traqueia/diagnóstico por imagem , Estudos Retrospectivos , Aorta Torácica/diagnóstico por imagem , Feto , Ultrassonografia Pré-NatalRESUMO
BACKGROUND: Combinational therapy such as taking tranexamic acid while using laser treatment has been proved potential efficacy by many experiments. However, there is few research which contains large samples and consistent observations. OBJECTIVE: We evaluated clinical efficacy and safety of a new systemic treatment of drug-laser-photon therapy. METHODS: Retrospective and randomized investigator-blinded study of 75 patients with mixed type melasma was analyzed. At each visit, standardized photographs were taken using VISIA. Modified melasma area and severity index (mMASI) scores were marked using photographs by two dermatologists. RESULTS: The mMASI score decreased significantly from 6.92 to 3.84 after the treatment. The VISIA analyze right cheek data shows: Spots (from 49.67 ± 3.43 to 56.09 ± 3.31), UV spots (from 41.39 ± 24.45 to 44.56 ± 25.86), and Brown spots (from 23.97 ± 17.89 to 28.16 ± 21.28) are statistically increased (p = 0.035, p = 0.018, p = 0.07). All patients feel varying degrees of improvement, about 10.17% felt very much improved, 30.51% felt much improved (51%-75%), 45.76% felt moderately improved (26%-50%), and 13.56% felt little improved (1%-25%). LIMITATIONS: This study was no control group. CONCLUSION: The efficacy and safety profile of the combination of drug-laser-photon therapy systemic treatment in melasma patients has been proved. It has potential possibility to become a new, reliable, widely suitable therapy strategy.
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Terapia a Laser , Lasers de Estado Sólido , Melanose , Humanos , Lasers de Estado Sólido/uso terapêutico , Melanose/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Background: Increasing evidence illustrated that m6A regulator-mediated modification plays a crucial role in regulating tumor immune and angiogenesis microenvironment. And the combination of immune checkpoint inhibitor and anti-angiogenic therapy has been approved as new first-line therapy for advanced HCC. This study constructed a novel prognosis signature base on m6A-mediated modification and explored the related mechanism in predicting immune and anti-angiogenic responses. Methods: Gene expression profiles and clinical information were collected from TCGA and GEO. The ssGSEA, MCPCOUNT, and TIMER 2.0 algorithm was used to Estimation of immune cell infiltration. The IC50 of anti-angiogenic drugs in GDSC was calculated by the "pRRophetic" package. IMvigor210 cohort and Liu et al. cohort were used to validate the capability of immunotherapy response. Hepatocellular carcinoma single immune cells sequencing datasets GSE140228 were collected to present the expression landscapes of 5 hub genes in different sites and immune cell subpopulations of HCC patients. Results: Three m6A clusters with distinct immune and angiogenesis microenvironments were identified by consistent cluster analysis based on the expression of m6A regulators. We further constructed a 5-gene prognosis signature (termed as m6Asig-Score) which could predict both immune and anti-angiogenic responses. We illustrated that high m6Asig-Score is associated with poor prognosis, advanced TNM stage, and high TP53 mutation frequency. Besides, the m6Asig-Score was negatively associated with immune checkpoint inhibitors and anti-angiogenic drug response. We further found that two of the five m6Asig-Score inner genes, B2M and SMOX, were associated with immune cell infiltration, immune response, and the sensitivity to sorafenib, which were validated in two independent immunotherapy cohorts and the Genomics of Drug Sensitivity in Cancer (GDSC) database. Conclusion: We constructed a novel prognosis signature and identified B2M and SMOX for predicting immune and anti-angiogenic efficacy in HCC, which may guide the combined treatment strategies of immunotherapy and anti-angiogenic therapy in HCC.
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BACKGROUND: Fetal growth restriction (FGR) occurs in up to 10% of pregnancies and is a leading cause of perinatal mortality and neonatal morbidity. Three-dimensional ultrasonography of intracranial structure volume revealed significant differences between fetuses with FGR and appropriate for gestational age (AGA) fetuses. We aimed to compare the frontal lobe development between fetuses with FGR and appropriately grown fetuses and evaluate the impact of fetal circulatory redistribution (FCR) on frontal lobe development in fetuses with FGR. METHODS: We performed a case-control study at our institution from August 2020 to April 2021. The frontal antero-posterior diameter (FAPD) and occipito-frontal diameter (OFD) were measured on the trans-ventricle view and we calculated the Z-scores for FAPD and OFD standardized for gestational age (GA) and transverse cerebellar diameter (TCD) by performing a standard regression analysis followed by weighted regression of absolute residual values in appropriately grown fetuses. We calculated the FAPD/OFD ratio as 100 × FAPD/OFD and FAPD/HC (head circumference) as 100 × FAPD/HC. To compare intracranial parameters, we randomly selected a control group of appropriately grown fetuses matched with the FGR group at the time of ultrasonography. We performed between-group comparisons of the FAPD Z-score, OFD Z-score, FAPD/OFD ratio and FAPD/HC. Similarly, we compared intracranial parameters between fetuses with FGR with and without FCR. RESULTS: FAPD/OFD ratio was curvilinear related to all the independent variables (GA, BPD, FL, and TCD). Compared with appropriately grown fetuses, fetuses with FGR showed a significantly lower FAPD/OFD ratio, FAPD Z-score, and FAPD/HC. There was no significant difference in the FAPD Z-score, FAPD/OFD ratio, and FAPD/HC between FGR fetuses with and without FCR. CONCLUSIONS: The FAPD/OFD ratio varied during pregnancy, with a mild reduction before and a mild increase after about 33 gestational weeks. Fetuses with FGR showed reduced frontal lobe growth; moreover, fetal frontal lobe development disorders were not significantly different in fetuses with FCR. TRIAL REGISTRATION: Date: 09-27-2017; Number: [2017]239.
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Doenças do Recém-Nascido , Ultrassonografia Pré-Natal , Gravidez , Recém-Nascido , Feminino , Humanos , Estudos de Casos e Controles , Ultrassonografia Pré-Natal/métodos , Feto , Ultrassonografia , Retardo do Crescimento Fetal/diagnóstico por imagem , Lobo FrontalRESUMO
Background: Copper metabolism plays an important role in the tumor microenvironment, and cuproptosis is the last discovered programmed cell death process. However, the potential mechanism of cuproptosis in regulating the immune microenvironment of HCC remains unclear. Methods: A total of 716 HCC patients with complete mRNA expression and survival information were collected from three public HCC cohorts (TCGA-LIHC cohort, n = 370; GSE76427 cohort, n = 115; ICGC-LIRI cohort, n = 231). The unsupervised clustering analysis (NMF) was performed to identify three different cuproptosis-related subtypes. The univariate-Cox, lasso-Cox and multivariate-Cox regression analyses were performed to screen the cuproptosis related and construct the cuproptosis-related prognosis signature (Cu-PS). The immune cell infiltration was estimated by both CIBERSORT and MCPcounter algorithms. Results: This study identified three distinct cuproptosis-related metabolic patterns, which presented different pathway enrichment and immune cell infiltration. The Cu-PS, a 5-genes (C7, MAGEA6, HK2, CYP26B1 and EPO) signature, was significantly associated with TNM stage, tumor mutational burden (TMB), drugs sensitivity, and immunotherapies response. Conclusion: This study performed a multi-genetic analysis of cuproptosis-related genes and further explored the regulatory mechanism of cuproptosis in HCC. The Cu-PS might be a useful biomarker for predicting immunotherapy response and enhancing the diagnosis and treatment of HCC.
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BACKGROUND: The critical diagnostic criteria for esophagogastric junction outflow obstruction (EGJOO) were published in the latest Chicago Classification version 4.0 (CCv4.0). In addition to the previous criterion [elevated integrated relaxation pressure (IRP) in supine position], manometric diagnosis of EGJOO requires meeting the criteria of elevated median-IRP during upright wet swallows and elevated intrabolus pressure. However, with the diagnostic criteria modification, the change in manometric features of EGJOO remained unclear. AIM: To evaluate the esophageal motility characteristics of patients with EGJOO and select valuable parameters for confirming the diagnosis of EGJOO. METHODS: We performed a retrospective analysis of 370 patients who underwent high-resolution manometry with 5 mL water swallows × 10 in supine, × 5 in upright position and the rapid drink challenge (RDC) with 200 mL water from November 2016 to November 2021 at Peking University First Hospital. Fifty-one patients with elevated integrated supine IRP and evidence of peristalsis were enrolled, with 24 patients meeting the updated manometric EGJOO diagnosis (CCv4.0) as the EGJOO group and 27 patients not meeting the updated EGJOO criteria as the isolated supine IRP elevated group (either normal median IRP in upright position or less than 20% of supine swallows with elevated IBP). Forty-six patients with normal manometric features were collected as the normal high-resolution manometry (HRM) group. Upper esophageal sphincter (UES), esophageal body, and lower esophageal sphincter (LES) parameters were compared between groups. RESULTS: Compared with the normal HRM group, patients with EGJOO (CCv4.0) had significantly lower proximal esophageal contractile integral (PECI) and proximal esophageal length (PEL), with elevated IRP on RDC (P < 0.05 for each comparison), while isolated supine IRP elevated patients had no such feature. Patients with EGJOO also had more significant abnormalities in the esophagogastric junction than isolated supine IRP elevated patients, including higher LES resting pressure (LESP), intrabolus pressure, median supine IRP, median upright IRP, and IRP on RDC (P < 0.05 for each comparison). Patients with dysphagia had significantly lower PECI and PEL than patients without dysphagia among the fifty-one with elevated supine IRP. Further multivariate analysis revealed that PEL, LESP, and IRP on RDC are factors associated with EGJOO. The receiver-operating characteristic analysis showed UES nadir pressure, PEL, PECI, LESP, and IRP on RDC are parameters supportive for confirming the diagnosis of EGJOO. CONCLUSION: Based on CCv4.0, patients with EGJOO have more severe esophagogastric junction dysfunction and are implicated in the proximal esophagus. Additionally, several parameters are supportive for confirming the diagnosis of EGJOO.
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Transtornos de Deglutição , Transtornos da Motilidade Esofágica , Gastropatias , Transtornos da Motilidade Esofágica/complicações , Esfíncter Esofágico Inferior , Junção Esofagogástrica , Humanos , Manometria , Estudos Retrospectivos , Gastropatias/complicações , ÁguaRESUMO
Background: Few studies have investigated the associations of childhood growth trajectories with the prenatal metabolic risks of mothers and their interaction with children's genetic susceptibility. Objective: To investigate the effects of gestational metabolic syndrome (GMS) risks and children's polygenic risk scores (PRSs), and their interaction effect on the BMI trajectory and obesity risk of offspring from birth to 6 years of age. Methods: A total of 2,603 mother-child pairs were recruited from the Ma'anshan birth cohort (Anhui Province of China) study. Data on maternal prepregnancy obesity, gestational weight gain (GWG), gestational diabetes mellitus (GDM), and hypertensive disorders of pregnancy (HDP) were used to evaluate maternal GMS risk. In addition, 1,482 cord blood samples were used to genotype 11 candidate single-nucleotide polymorphisms (SNPs) to calculate children's PRSs. The latent class growth model using the longitudinal BMI-for-age z scores (BMIz) was applied to validly capture the BMIz growth trajectory. Results: Maternal GMS status was associated with higher BMIz scores and with an increased risk of overweight/obesity. Positive relationships were revealed between PRS and the risk of overweight/obesity among girls. Additionally, maternal GMS significantly interacted with the child's PRS on BMIz scores and the risk of overweight/obesity among girls. Hierarchical BMI trajectory graphs by different exposure groups showed consistent findings, and both boys' and girls' BMIz trajectories were divided into three groups. Among girls, the higher the GMS risk or PRS they had, the higher the probability of being in the high BMIz trajectory group. Conclusions: Maternal GMS status increased BMIz scores and the risk of obesity in both boys and girls and elevated the child's BMI trajectory from birth to 6 years of age among girls. PRSs were significantly associated with children's BMI trajectory and the risk of obesity and modified the associations between maternal GMS status and obesity biomarkers only among girls. Thus, regarding childhood obesity, steps should be taken to decrease maternal metabolic risks before and during pregnancy, and sex discrepancies should be noted to identify high-risk populations after birth to hierarchically manage them.
Assuntos
Síndrome Metabólica , Obesidade Materna , Obesidade Infantil , Coorte de Nascimento , Índice de Massa Corporal , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/genética , Sobrepeso/complicações , Obesidade Infantil/complicações , GravidezRESUMO
OBJECTIVE: We aim to establish a formula calculating the fetal cavum septi pellucidi (CSP) width Z-scores and compare CSP width between the normal fetus and 18-trisomy fetus. METHODS: In this retrospective study, 608 normal fetuses and 71 fetuses with the 18-trisomy syndrome were included. Z-scores were calculated after the acquisition of CSP images. Normal CSP width Z-scores formulae were constructed based on gestational age (GA) by performing a standard regression analysis followed by weighted regression of absolute residual values. Subsequently, the Mann-Whitney U test was used to compare the CSP width Z-scores between normal and 18-trisomy groups. RESULTS: Formulae calculating CSP width Z-scores were constructed. Normal fetal CSP width was significantly correlated with GA (R2 = 0.50, p < .01). In 18-trisomy group, 69% (34/49) fetuses displayed enlarged fetal CSP width and CSP width Z-scores (p < .01). CONCLUSIONS: The CSP width Z-scores formulae established in the current study can provide a quantitative basis for the prenatal diagnosis of 18-trisomy syndrome. Enlarged CSP width Z-score may serve as a novel prenatal diagnostic marker for the 18-trisomy syndrome.
Assuntos
Septo Pelúcido , Ultrassonografia Pré-Natal , Feminino , Feto/diagnóstico por imagem , Humanos , Gravidez , Estudos Retrospectivos , Septo Pelúcido/diagnóstico por imagem , Síndrome da Trissomía do Cromossomo 18RESUMO
Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in immune regulation. Growing evidence suggests that immune-related genes and lncRNAs can serve as markers to predict the prognosis of patients with cancers, including hepatocellular carcinoma (HCC). This study aimed to contract an immune-related lncRNA (IR-lncRNA) signature for prospective assessment to predict early recurrence of HCC. A total of 319 HCC samples under radical resection were randomly divided into a training cohort (161 samples) and a testing cohort (158 samples). In the training dataset, univariate, lasso, and multivariate Cox regression analyses identified a 9-IR-lncRNA signature closely related to disease-free survival. Kaplan-Meier analysis, principal component analysis, gene set enrichment analysis, and nomogram were used to evaluate the risk model. The results were further confirmed in the testing cohort. Furthermore, we constructed a competitive endogenous RNA regulatory network. The results of the present study indicated that this 9-IR-lncRNA signature has important clinical implications for improving predictive outcomes and guiding individualized treatment in HCC patients. These IR-lncRNAs and regulated genes may be potential biomarkers associated with the prognosis of HCC.