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Liver transplantation (LT) is an ideal therapeutic option for selected patients with hepatocellular carcinoma (HCC). The selection criteria of HCC for LT have evolved in recent decades. Downstaging therapy is a promising strategy for patients with tumor burden beyond transplant criteria to increase the chance of receiving LT and improve posttransplant survival. Downstaging therapy is also a selection tool that refines the conventional selection criteria based on tumor morphology. Recently, the success of systemic treatment, including immune checkpoint inhibitors, antiangiogenic tyrosine kinase inhibitors, and VEGF inhibitors, in advanced HCC has prompted the discussion regarding the role of systemic therapies for HCC downstaging before transplantation. In this review, we aimed to summarize the current advances in selection criteria and therapeutic options of downstaging therapy for HCC before LT.
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Background: Osteoporosis (OP) associated with aging exerts substantial clinical and fiscal strains on societal structures. An increasing number of research studies have suggested a bidirectional relationship between circulating inflammatory markers (CIMs) and OP. However, observational studies are susceptible to perturbations in confounding variables. In contrast, Mendelian randomization (MR) offers a robust methodological framework to circumvent such confounders, facilitating a more accurate assessment of causality. Our study aimed to evaluate the causal relationships between CIMs and OP, identifying new approaches and strategies for the prevention, diagnosis and treatment of OP. Methods: We analyzed publicly available GWAS summary statistics to investigate the causal relationships between CIMs and OP. Causal estimates were calculated via a systematic analytical framework, including bidirectional MR analysis and Bayesian colocalization analysis. Results: Genetically determined levels of CXCL11 (OR = 0.91, 95% CI = 0.85-0.98, P = 0.008, PFDR = 0.119), IL-18 (OR = 0.88, 95% CI = 0.83-0.94, P = 8.66×10-5, PFDR = 0.008), and LIF (OR = 0.86, 95% CI = 0.76-0.96, P = 0.008, PFDR = 0.119) were linked to a reduced risk of OP. Conversely, higher levels of ARTN (OR = 1.11, 95% CI = 1.02-1.20, P = 0.012, PFDR = 0.119) and IFNG (OR = 1.16, 95% CI = 1.03-1.30, P = 0.013, PFDR = 0.119) were associated with an increased risk of OP. Bayesian colocalization analysis revealed no evidence of shared causal variants. Conclusion: Despite finding no overall association between CIMs and OP, five CIMs demonstrated a potentially significant association with OP. These findings could pave the way for future mechanistic studies aimed at discovering new treatments for this disease. Additionally, we are the first to suggest a unidirectional causal relationship between ARTN and OP. This novel insight introduces new avenues for research into diagnostic and therapeutic strategies for OP.
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Biomarcadores , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Osteoporosis , Humanos , Osteoporosis/sangre , Osteoporosis/genética , Osteoporosis/etiología , Osteoporosis/diagnóstico , Biomarcadores/sangre , Teorema de Bayes , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Inflamación/sangre , Inflamación/genética , FemeninoRESUMEN
Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS- tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS- tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.
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Quimiocina CCL19 , Neoplasias Colorrectales , Inmunoglobulina G , Neoplasias Hepáticas , Estructuras Linfoides Terciarias , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Animales , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Ratones , Inmunoglobulina G/inmunología , Quimiocina CCL19/metabolismo , Quimiocina CCL19/genética , Fibroblastos/metabolismo , Fibroblastos/inmunología , Anticuerpos Monoclonales/farmacología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Femenino , Línea Celular TumoralRESUMEN
OBJECTIVE: This study aimed to assess the use of two-dimensional (2D) ultrasound combined with high-definition flow (HD-flow) render mode and spatiotemporal image correlation (STIC) in diagnosing and classifying fetal persistent left superior vena cava (PLSVC). METHODS: Overall, 114 cases of fetal PLSVC were diagnosed using 2D ultrasound combined with STIC, and 114 normal fetuses of the same gestational week were selected. These cases were retrospectively analyzed to evaluate the effectiveness of the diagnostic approach. RESULTS: All 114 PLSVC cases were diagnosed using 2D ultrasound combined with STIC. Although the diagnostic coincidence rate of PLSVC in the HD-flow combined with STIC was similar to that in the 2D ultrasound combined with HD-flow (96.8 vs 96.2%), 2D ultrasound with STIC enabled dynamic visualization of the PLSVC, furthering prenatal diagnosis. These cases were classified as type I PLSVC: 80 cases of type Ia, 29 cases of type Ib, and 5 cases of type Ic. Seventy isolated PLSVC cases (61.4%) were noted, whereas 44 cases (35.6%) were associated with concomitant structural abnormalities. Intracardiac structural malformations accounted for the highest proportion (n = 53, 58.89%), followed by single umbilical artery and facial/bodily abnormalities (n = 10, 11.11%). CONCLUSION: Combining HD-flow and STIC complements 2D ultrasound in diagnosing and classifying fetal PLSVC, demonstrating significant clinical relevance.
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Supercapacitors (SCs) have received widespread attention as excellent energy storage devices, and the design of multicomponent electrode materials and the construction of ingenious structures are the keys to enhancing the performance of SCs. In this paper, MoS2 nanorods were used as the carrier structure to induce the anchoring of CoAl-LDH nanosheets and grow on the surface of nickel foam (NF) in situ, thus obtaining a uniformly distributed MoS2 nanorod@CoAl-LDH nanosheet core-shell nanoarray material (MoS2@CoAl-LDH/NF). On the one hand, the nanorod-structured MoS2 as the core provides high conductivity and support, accelerates electron transfer, and avoids agglomeration of CoAl-LDH nanosheets. On the other hand, CoAl-LDH nanosheet arrays have abundant interfacially active sites, which accelerate the electrolyte penetration and enhance the electrochemical activity. The synergistic effect of the two components and the unique core-shell nanostructure give MoS2@CoAl-LDH/NF a high capacity (14,888.8 mF cm-2 at 2 mA cm-2) and long-term cycling performance (104.4% retention after 5000 charge/discharge cycles). The integrated MoS2@CoAl-LDH/NF//AC device boasts a voltage range spanning from 0 to 1.5 V, achieving a peak energy density of 0.19 mW h cm-2 at 1.5 mW cm-2. Impressively, it maintains a capacitance retention rate of 84.6% after enduring 10,000 cycles, demonstrating exceptional durability and stability.
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OBJECTIVES: To evaluate the clinical utility of two dimensional (2D) ultrasound combined with spatiotemporal image correlation (STIC) in diagnosing interrupted aortic arch (IAA) in fetal life. METHODS: A total of 53 cases of fetal IAA were diagnosed using 2D ultrasound combined with STIC, and 53 normal fetuses of the same gestational week were selected. These cases were retrospectively analyzed to assess the utility of employing 2D ultrasound combined with STIC in the diagnosis of IAA. RESULTS: 2D ultrasound combined with STIC detected 22 cases of type A IAA, 24 cases of type B IAA, and seven cases of type C IAA. Furthermore, combining 2D ultrasound with STIC enabled dynamic visualization of the IAA, aiding in prenatal diagnosis. The diagnostic coincidence rate of IAA was found to be higher in the HD-flow combined with STIC than that in the 2D combined with HD-flow. CONCLUSION: HD-flow combined with STIC can assist in diagnosing fetal IAA, and this technique has important clinical value.
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Aorta Torácica , Ultrasonografía Prenatal , Humanos , Femenino , Ultrasonografía Prenatal/métodos , Embarazo , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/anomalías , Aorta Torácica/embriología , Estudios Retrospectivos , Adulto , Reproducibilidad de los Resultados , Corazón Fetal/diagnóstico por imagenRESUMEN
BACKGROUND AND AIMS: Lymph node metastasis is a significant risk factor for patients with cholangiocarcinoma, but the mechanisms underlying cholangiocarcinoma colonization in the lymph node microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled the adaptation and remodeling of cholangiocarcinoma cells to the lymph node microenvironment. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing of primary tumor lesions and paired lymph node metastases from patients with cholangiocarcinoma and revealed significantly reduced intertumor heterogeneity and syntropic lipid metabolic reprogramming of cholangiocarcinoma after metastasis to lymph nodes, which was verified by pan-cancer single-cell RNA sequencing analysis, highlighting the essential role of lipid metabolism in tumor colonization in lymph nodes. Metabolomics and in vivo CRISPR/Cas9 screening identified PPARγ as a crucial regulator in fueling cholangiocarcinoma colonization in lymph nodes through the oleic acid-PPARγ-fatty acid-binding protein 4 positive feedback loop by upregulating fatty acid uptake and oxidation. Patient-derived organoids and animal models have demonstrated that blocking this loop impairs cholangiocarcinoma proliferation and colonization in the lymph node microenvironment and is superior to systemic inhibition of fatty acid oxidation. PPARγ-regulated fatty acid metabolic reprogramming in cholangiocarcinoma also contributes to the immune-suppressive niche in lymph node metastases by producing kynurenine and was found to be associated with tumor relapse, immune-suppressive lymph node microenvironment, and poor immune checkpoint blockade response. CONCLUSIONS: Our results reveal the role of the oleic acid-PPARγ-fatty acid-binding protein 4 loop in fueling cholangiocarcinoma colonization in lymph nodes and demonstrate that PPARγ-regulated lipid metabolic reprogramming is a promising therapeutic target for relieving cholangiocarcinoma lymph node metastasis burden and reducing further progression.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Proteínas de Unión a Ácidos Grasos , Metástasis Linfática , Ácido Oléico , PPAR gamma , Microambiente Tumoral , Colangiocarcinoma/patología , Colangiocarcinoma/metabolismo , PPAR gamma/metabolismo , Humanos , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Animales , Proteínas de Unión a Ácidos Grasos/metabolismo , Ratones , Ganglios Linfáticos/patología , Metabolismo de los LípidosRESUMEN
Bacterial infections, viral infections and autoimmune diseases pose a considerable threat to human health. Procalcitonin (PCT) has emerged as a biomarker for the detection of these diseases. To ensure accurate and reliable results, we propose a dual-mode approach that incorporates self-validation and self-correction mechanisms. Herein, we develop a dual-mode self-powered photoelectrochemical (PEC) and colorimetric sensor to determine PCT. The self-powered PEC sensor was constructed with a photoanode of spherical nanoflower-MoS2/Cu2ZnSnS4/Bi2S3 material and a photocathode of CuInS2 material. Ni4Cu2 bimetallic hollow nanospheres (BHNs) possess superoxide dismutase and catalase performance, which facilitate superoxide anion radical (·O2-) and H2O2 circulating generation, promoting the separation of photogenerated electrons and holes to amplify photocurrent signal. Thus Ni4Cu2 BHNs is used as a marker material for PEC sensor. Meanwhile, in colorimetric mode, Ni4Cu2 BHNs converts blue oxTMB to a colourless TMB for colorimetric detection of PCT. Based on this principle, dual-mode determination of PCT with high sensitivity is achieved. The dual-mode method not only demonstrates outstanding properties and practicability, but also presents an effective, highly efficient and reliable method for detecting PCT.
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Técnicas Biosensibles , Nanosferas , Humanos , Nanosferas/química , Polipéptido alfa Relacionado con Calcitonina , Molibdeno/química , Peróxido de Hidrógeno , Colorimetría , Técnicas Electroquímicas/métodos , Técnicas Biosensibles/métodos , Límite de DetecciónRESUMEN
INTRODUCTION: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare autosomal dominant disorder characterized by megalencephaly (i.e., overgrowth of the brain), polymicrogyria, focal hypoplasia of the cerebral cortex, and polydactyly. Persistent hyperplastic primary vitreous (PHPV) involves a spectrum of congenital ocular abnormalities that are characterized by the presence of a vascular membrane behind the lens. CASE PRESENTATION: Here, we present a case of foetal MPPH with PHPV that was diagnosed using prenatal ultrasound. Ultrasound revealed the presence of megalencephaly, multiple cerebellar gyri, and hydrocephalus. Whole-exome sequencing confirmed the mutation of the AKT3 gene, which led to the consideration of MPPH syndrome. Moreover, an echogenic band with an irregular surface was observed between the lens and the posterior wall of the left eye; therefore, MPPH with PHPV was suspected. CONCLUSION: MPPH syndrome with PHPV can be diagnosed prenatally.
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Hidrocefalia , Malformaciones del Desarrollo Cortical , Megalencefalia , Vítreo Primario Hiperplásico Persistente , Polidactilia , Polimicrogiria , Embarazo , Femenino , Humanos , Polimicrogiria/diagnóstico por imagen , Polimicrogiria/genética , Vítreo Primario Hiperplásico Persistente/diagnóstico por imagen , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical/diagnóstico , Malformaciones del Desarrollo Cortical/genética , Hidrocefalia/diagnóstico por imagen , Megalencefalia/genética , Polidactilia/diagnóstico por imagen , Polidactilia/genética , Síndrome , Ultrasonografía PrenatalRESUMEN
BACKGROUND: Both closed platform and open platform robotic-assisted total hip arthroplasty (THA) have recently been recommended as a viable treatment option for achieving accurate positioning of components. Yet, limited studies paid attention to the differences between the closed platform robotic system and the open platform robotic system. Hence, this study aimed to investigate clinical outcomes, radiographic outcomes, complication rates and learning curve of two systems. MATERIALS AND METHODS: We retrospectively included 62 patients (31 closed robotic system and 31 open robotic system) who underwent THA between February 2021 and January 2023. The demographics, operating time, cup positioning, complications and hip Harris score were evaluated. Learning curves of operation time was conducted using cumulative sum (CUSUM) analysis. RESULTS: There were no differences in surgical time (76.7 ± 12.1 min vs. 72.3 ± 14.8 min), estimated blood loss (223.2 ± 13.2 ml vs. 216.9 ± 17 ml) and Harris Hip score (HHS) between closed platform robotic system and the open platform robotic system. The closed robotic system and the open robotic system were associated with a learning curve of 9 cases and 7 cases for surgical time respectively, based on the satisfying rate of Lewinnek's safe zone outliers (1/31, 96.8%) and no occurrence of complication. Both robotic systems had significant reduction in overall surgical time, the duration of acetabulum registration, and estimated blood loss between learning phase and proficiency phase. CONCLUSION: The authors suggest that the surgical outcomes and safe zone outlier rate of the open robotic-assisted THA were similar to those of the closed robotic-assisted THA. These two robotic-assisted are associated with comparable learning curves and both have the precise positioning of acetabular component. From learning phase to proficiency phase, the rate of positions within the safe zone differed only marginally (88.9-100% vs. 85.7-100%) based on a rather low number of patients. This is not a statistically significant difference. Therefore, we suggest that THA undergoing with the robotic-assisted system is the relatively useful way to achieve planned acetabular cup position so far.
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Artroplastia de Reemplazo de Cadera , Procedimientos Quirúrgicos Robotizados , Humanos , Curva de Aprendizaje , Artroplastia de Reemplazo de Cadera/efectos adversos , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversos , AcetábuloRESUMEN
Transition metal selenides (TMSs) are viewed as a prospective high-capacity electrode material for asymmetric supercapacitors (ASCs). However, the inability to expose sufficient active sites due to the limitation of the area involved in the electrochemical reaction severely limits their inherent supercapacitive properties. Herein, a self-sacrificing template strategy is developed to prepare self-supported CuCoSe (CuCoSe@rGO-NF) nanosheet arrays by in situ construction of copper-cobalt bimetallic organic framework (CuCo-MOF) on rGO-modified nickel foam (rGO-NF) and rational design of Se2- exchange process. Nanosheet arrays with high specific surface area are considered to be ideal platforms for accelerating electrolyte penetration and exposing rich electrochemical active sites. As a result, the CuCoSe@rGO-NF electrode delivers a high specific capacitance of 1521.6 F/g at 1 A/g, good rate performance and an excellent capacitance retention of 99.5% after 6000 cycles. The assembled ASC device has a high energy density of 19.8 Wh kg-1 at 750 W kg-1 and an ideal capacitance retention of 86.2% after 6000 cycles. This proposed strategy offers a viable strategy for designing and constructing electrode materials with superior energy storage performance.
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It has been reported that Akkermansia muciniphila improves host metabolism and reduces inflammation; however, its potential effects on bile acid metabolism and metabolic patterns in metabolic-associated fatty liver disease (MAFLD) are unknown. In this study, we have analysed C57BL/6 mice under three feeding conditions: (i) a low-fat diet group (LP), (ii) a high-fat diet group (HP) and (iii) a high-fat diet group supplemented with A. muciniphila (HA). The results found that A. muciniphila administration relieved weight gain, hepatic steatosis and liver injury induced by the high-fat diet. A. muciniphila altered the gut microbiota with a decrease in Alistipes, Lactobacilli, Tyzzerella, Butyricimonas and Blautia, and an enrichment of Ruminiclostridium, Osclibacter, Allobaculum, Anaeroplasma and Rikenella. The gut microbiota changes correlated significantly with bile acids. Meanwhile, A. muciniphila also improved glucose tolerance, gut barriers and adipokines dysbiosis. Akkermansia muciniphila regulated the intestinal FXR-FGF15 axis and reshaped the construction of bile acids, with reduced secondary bile acids in the caecum and liver, including DCA and LCA. These findings provide new insights into the relationships between probiotics, microflora and metabolic disorders, highlighting the potential role of A. muciniphila in the management of MAFLD.
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Microbioma Gastrointestinal , Hepatopatías , Enfermedades Metabólicas , Animales , Ratones , Dieta Alta en Grasa/efectos adversos , Ácidos y Sales Biliares/farmacología , Ratones Endogámicos C57BL , VerrucomicrobiaRESUMEN
In this study, a ratiometric electrochemical immunosensor has been developed to detect the cytokeratin 19 fragment 21-1 (CYFRA21-1) biomarker in a highly sensitive manner through a dual-signal output model. As one of signal indicators, snowflake-like FeSe2 loaded with AuNPs (FeSe2-AuNPs) as sensing substrate with good conductivity and large active sites provides a differential pulse voltammetry (DPV) signal at +0.4 V. Another signal indicator, toluidine blue (TB) with the water-solubility property is an excellent redox probe that can generate DPV signal at -0.3 V. To solve the water-solubility problem, the TB is absorbed with polyacrylic acid (PAA) functionalized ZIF-67 (PAA-ZIF-67), which retains the properties of ZIF-67 that are large specific surface area and strong adsorption properties. The ratio of signals, stemmed from PAA-ZIF@TB and FeSe2-AuNPs (IPAA-ZIF@TB/IFeSe2-AuNPs), increases with the CYFRA21-1 concentration. Under optimal experimental conditions, CYFRA21-1 was detected in a wide dynamic range from 0.1 pg/mL to 100 ng/mL, with a lower limit of detection of 0.02 pg/mL. Looking ahead, this ratio based strategy provides prospective clinical applications for detecting other biomarkers.
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Técnicas Biosensibles , Grafito , Nanopartículas del Metal , Grafito/química , Técnicas Electroquímicas , Oro/química , Cloruro de Tolonio , Estudios Prospectivos , Inmunoensayo , Nanopartículas del Metal/química , Agua , Límite de DetecciónRESUMEN
INTRODUCTION: To explore the diagnostic value of spatiotemporal image correlation (STIC) for different types of fetal conotruncal defects (CTDs). METHODS: The clinical data and STIC images of 174 fetuses with CTDs diagnosed via prenatal ultrasound were analyzed retrospectively. RESULTS: Among the 174 cases of CTDs, 58 were tetralogy of Fallot (TOF); 30, transposition of great arteries (TGA) (D-TGA, 23 cases; cc-TGA, 7 cases); 26, double outlet of the right ventricle (DORV); 32, persistent arterial trunk (PTA) (type A1, 15 cases; type A2, 11 cases; type A3, 5 cases; type A4, 1 case); and 28, pulmonary atresia (PA) (ventricular septal defect, 24 cases; ventricular septal integrity, 4 cases). Among the cases, 156 were complicated with complex congenital intracardiac and extracardiac malformations. The abnormal display rate of the four-chamber view of two-dimensional echocardiography was low. The display rate of the permanent arterial trunk was the highest (90.6%) in STIC imaging. CONCLUSIONS: STIC imaging can be used in the diagnosis of different types of CTDs, especially in persistent arterial trunks, and thus has great value for the clinical treatment and prognosis of these defects.
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Ventrículo Derecho con Doble Salida , Cardiopatías Congénitas , Transposición de los Grandes Vasos , Embarazo , Femenino , Humanos , Estudios Retrospectivos , Ultrasonografía Prenatal/métodos , Diagnóstico Prenatal , Transposición de los Grandes Vasos/diagnóstico por imagen , FetoRESUMEN
BACKGROUND: Kidneys from very small pediatric donors (VSPDs, aged <2 y) are underutilized. Concerns regarding potentially inferior outcomes hinder the use in pediatric recipients. METHODS: All pediatric kidney-only transplants from <18-year-old donors between January 2012 and May 2021 in our center were included in this study. Outcomes were compared between VSPD and normal pediatric donor (NPD, aged 2-18 y) groups, and 3-y death-censored graft survival was assessed by the multivariable Cox proportional hazard model. RESULTS: Of all 252 enrolled patients, 149 (59.1%) received kidneys from NPDs and 103 (40.9%) from VSPDs. The 3-y graft survival rates of the NPD and VSPD groups were 91.2% and 88.6%, respectively ( P = 0.385). The adjusted hazard ratio of 3-y graft loss was 1.2 (95% confidence interval, 0.6-2.5; P = 0.659) for the VSPD group compared with the NPD group. There was no significant difference in estimated glomerular filtration rate at 3 y posttransplant observed between NPD and VSPD groups (86.9 ± 26.8 versus 87 ± 27.9 mL/min/1.73 m 2 ; P = 0.991). Patients (n = 12, 4.8%) who received kidneys from donors <5 kg contributed 5 (5/39, 12.8%) with delayed graft function and the sole primary nonfunction in our cohort. CONCLUSIONS: Although attention to preventing complications is necessary, especially for kidneys from donors <5 kg, kidneys from VSPDs did not appear to impart added risk for 3-y graft loss and renal function.
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Trasplante de Riñón , Humanos , Niño , Adolescente , Trasplante de Riñón/efectos adversos , Selección de Donante , Riñón/fisiología , Donantes de Tejidos , Supervivencia de Injerto , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
Background and Aims: Patients with persistent positive hepatitis B surface antigen (HBsAg), even with a low HBV-DNA load, have a higher risk of hepatocellular carcinoma (HCC) than those without HBV infection. Given that tumor stemness has a critical role in the occurrence and maintenance of neoplasms, this study aimed to explore whether HBsAg affects biological function and stemness of HCC by regulating microRNA, and to explore underlying mechanisms. Methods: We screened out miR-203a, the most significant down-regulated microRNA in the microarray analysis of HBsAg-positive samples and focused on that miRNA in the ensuing study. In vitro and in vivo functional experiments were performed to assess its regulatory function. The effect of miR-203a on stemness and the possible correlation with BMI1 were analyzed in this study. Results: MiR-203a was significantly down-regulated in HBsAg-positive HCC with the sharpest decrease shown in microarray analysis. The negative correlation between miR-203a and HBsAg expression was confirmed by quantitative real-time PCR after stimulation or overexpression/knockdown of HBsAg in cells. We demonstrated the function of miR-203a in inhibiting HCC cell proliferation, migration, clonogenic capacity, and tumor development in vivo. Furthermore, the overexpression of miR-203a remarkably increases the sensitivity of tumor cells to 5-FU treatment and decreases the proportion of HCC cells with stem markers. In concordance with our study, the survival analysis of both The Cancer Genome Atlas database and samples in our center indicated a worse prognosis in patients with low level of miR-203a. We also found that BMI1, a gene maintains the self-renewal capacity of stem cells, showed a significant negative correlation with miR-203a in HCC specimen (p<0.001). Similarly, opposite BMI1 changes after overexpression/knockdown of miR-203a were also confirmed in vitro. Dual luciferase reporting assay suggested that miR-203a may regulate BMI1 expression by direct binding. Conclusions: HBsAg may promote the development of HCC and tumor stemness by inhibiting miR-203a, resulting in poor prognosis. miR-203a may serve as a crucial treatment target in HBsAg-positive HCC. More explicit mechanistic studies and animal experiments need to be conducted as a next step.
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BACKGROUND: Nephronophthisis-related ciliopathies (NPHP-RC) have strong genotype and phenotype heterogeneity, and the transplantation strategy of Boichis syndrome is still controversial. Our purpose was to examine associations of genotype and phenotype in children with NPHP-RC and analyze the transplantation strategies of different phenotypes. METHODS: The records of children with NPHP treated at our center from 01/2018 to 03/2021 were retrospectively reviewed. Inclusion criteria were a diagnosis of NPHP, received kidney transplantation, and received whole exome sequencing (WES) or nephropathy gene panel testing. RESULTS: Twenty-nine children with NPHP were included. Nine children (31%) had NPHP1 mutations, and all presented with isolated nephropathy. Eighteen of 20 patients with non-NPHP1 mutations had compound heterozygous mutations, and 70% had extrarenal phenotype. Age at disease presentation (11.2 ± 1.94 years) and the development of kidney failure (12.4 ± 2.70 years) were later in children with NPHP1 mutations than those with non-NPHP1 mutations (5.2 ± 2.83 years and 5.7 ± 2.92 years, respectively). Four of six children with NPHP3 mutations were diagnosed with Boichis syndrome due to liver fibrosis. Isolated kidney transplantation resulted in good outcomes for patients with mild or moderate liver fibrosis without portal hypertension, while cholestasis was common postoperatively and could be resolved with ursodeoxycholic acid. CONCLUSIONS: NPHP1 mutations are the most common in children with NPHP, and the phenotype of NPHP1 mutation is significantly different from that of non-NPHP1 mutation. For NPHP patients with mild to moderate liver fibrosis without portal hypertension, timely treatment of cholestasis could prevent the rapid progression of liver function damage after isolated kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Ciliopatías , Hipertensión Portal , Enfermedades Renales Quísticas , Enfermedades Renales Poliquísticas , Insuficiencia Renal , Niño , Humanos , Estudios Retrospectivos , Proteínas de la Membrana/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/cirugía , Enfermedades Renales Quísticas/complicaciones , Genotipo , Mutación , Fenotipo , Insuficiencia Renal/complicaciones , Ciliopatías/complicaciones , Cirrosis Hepática/complicacionesRESUMEN
Purpose: Bilateral Wilms tumor (BWT) with renal sinus invasion requires extremely difficult surgical care. This study presents an alternative strategy for tumor removal while at the same time preserving the renal parenchyma. Materials and methods: In total, 9 cases of synchronous BWT were admitted to our hospital between May 2016 to Aug 2020. We retrospectively reviewed the clinical data, surgical technique, and functional and oncological outcomes of these cases. Results: The 9 cases included 3 males and 6 females, with a median age of 12 months at surgery (range 7-40). A total of 14 kidney units had renal sinus invasion (77.8%), whereas multifocal neoplasms were observed in 7 units (38.9%). The local stage distribution revealed 1 kidney with stage I, 10 kidneys with stage II, and 7 kidneys with stage III. Nephron-sparing surgery was performed on 15 kidney units (83.3%), among which 13 (72.2%) underwent bench surgery with autotransplantation (BS-AT), whereas 2 (11.1%) were subjected to tumor enucleation in vivo. Urinary leakage was the most prevalent postoperative complication. We observed negative margins. During the mean follow-up of 28.4 months, 2 patients (22.2%) succumbed from sepsis and renal failure, respectively, whereas the other 7 (77.8%) survived without recurrence. Survivors experienced an estimated glomerular filtration rate of 81 ± 15.4â ml/(min × 1.73â m2). The endpoint renal volume of 9 renal units receiving BS-AT significantly increased (P = 0.02). Conclusions: In summary, the surgical management of bilateral Wilms tumor requires meticulous operative approach and technique. Besides, BS-AT provides a viable alternative to nephron-sparing surgery for BWT patients with renal sinus invasion.