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BACKGROUND: Although immunotherapy shows tremendous potential in the treatment of bladder cancer (BLCA), the overall prognosis and response rates to immunotherapy in BLCA remain suboptimal. METHODS: We performed an extensive evaluation of glycosyltransferase expression patterns in BLCA patients by analyzing 210 glycosyltransferase-related genes. Subsequently, we established correlations between these glycosyltransferase patterns, prognosis, and tumor microenvironment (TME) phenotypes. To offer personalized patient assessments, we developed a glycosyltransferase risk score that accurately predicts prognosis, TME phenotypes, and molecular subtypes. Importantly, we developed a RNA-seq cohort, named Xiangya cohort, to validate our results. RESULTS: Two distinct patterns of glycosyltransferase expression were identified, corresponding to inflamed and noninflamed TME phenotypes, and demonstrated the potential to predict prognosis. We developed and validated a comprehensive risk score that accurately predicted individual patient prognosis in the TCGA-BLCA cohort. Additionally, we constructed a nomogram that integrated the risk score with several key clinical factors. Importantly, this risk score was successfully validated in external cohorts, including the Xiangya cohort and GSE48075. Furthermore, we discovered a positive correlation between this risk score and tumor-infiltrating lymphocytes in both the TCGA-BLCA and Xiangya cohorts, suggesting that patients with a higher risk score exhibited an inflamed TME phenotype and were more responsive to immunotherapy. Finally, we observed that the high and low risk score groups were consistent with the luminal and basal subtypes of BLCA, respectively, providing further validation of the risk score's role in the TME in terms of molecular subtypes. CONCLUSIONS: Glycosyltransferase patterns exhibit distinct TME phenotypes in BLCA. Our comprehensive risk score provides a promising approach for prognostic prediction and assessment of immunotherapy efficacy, offering valuable guidance for precision medicine.
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Glicosiltransferases , Imunoterapia , Nomogramas , Fenótipo , Microambiente Tumoral , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/mortalidade , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Prognóstico , Imunoterapia/métodos , Glicosiltransferases/genética , Glicosiltransferases/metabolismo , Masculino , Feminino , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Medição de Risco , Idoso , Regulação Neoplásica da Expressão Gênica , Fatores de RiscoRESUMO
BACKGROUND: Human milk is unquestionably beneficial for preterm infants. We investigated how the transition from tube to oral/breastfeeding impacts the preterm infants' oral and gut microbiome and metabolome. METHODS: We analyzed stool, saliva, and milk samples collected from a cohort of preterm infants enrolled in the MAP Study, a prospective observational trial. The microbiome and metabolome of the samples were analyzed from 4 longitudinal sample time points, 2 during tube feeds only and 2 after the initiation of oral/breastfeeding. RESULTS: We enrolled 11 mother-infant dyads (gestational age = 27.9 (23.4-32.2)) and analyzed a total of 39 stool, 44 saliva, and 43 milk samples over 4 timepoints. In saliva samples, there was a shift towards increased Streptococcus and decreased Staphylococcus after oral feeding/breastfeeding initiation (p < 0.05). Milk sample metabolites were strongly influenced by the route of feeding and milk type (p < 0.05) and represented the pathways of Vitamin E metabolism, Vitamin B12 metabolism, and Tryptophan metabolism. CONCLUSION: Our analysis demonstrated that the milk and preterm infant's saliva microbiome and metabolome changed over the course of the first four to 5 months of life, coinciding with the initiation of oral/breastfeeds. IMPACT: The microbiome and metabolome is altered in the infant's saliva but not their stool, and in mother's milk when feeds are transitioned from tube to oral/breastfeeding. We assessed the relationship between the gut and oral microbiome/metabolome with the milk microbiome/metabolome over a longitudinal period of time in preterm babies. Metabolites that changed in the infants saliva after the initiation of oral feeds have the potential to be used as biomarkers for disease risk.
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BACKGROUND: Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. METHODS: Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. RESULTS: In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. CONCLUSIONS: In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. Video Abstract.
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Neoplasias da Próstata , Transdução de Sinais , Masculino , Animais , Humanos , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Neoplasias da Próstata/patologia , Via de Sinalização Hippo , Proliferação de Células , Mamíferos/metabolismo , Ataxina-3/metabolismo , Proteínas Repressoras/metabolismoRESUMO
Benign prostate hyperplasia (BPH) is the most commonly seen disease among aging males. Transforming growth factor(TGF)-ß-mediated epithelial-mesenchymal transition (EMT) and epithelial overproliferation might be central events in BPH etiology and pathophysiology. In the present study, long noncoding RNA MIR663AHG, miR-765, and FOXK1 formed a competing endogenous RNAs network, modulating TGF-ß-mediated EMT and epithelial overproliferation in BPH-1 cells. miR-765 expression was downregulated in TGF-ß-stimulated BPH-1 cells; miR-765 overexpression ameliorated TGF-ß-mediated EMT and epithelial overproliferation in BPH-1 cells. MIR663AHG directly targeted miR-765 and negatively regulated miR-765; MIR663AHG knockdown also attenuated TGF-ß-induced EMT and epithelial overproliferation in BPH-1 cells, whereas miR-765 inhibition attenuated MIR663AHG knockdown effects on TGF-ß-stimulated BPH-1 cells. miR-765 directly targeted FOXK1 and negatively regulated FOXK1. FOXK1 knockdown attenuated TGF-ß-induced EMT and epithelial overproliferation and promoted autophagy in BPH-1 cells, and partially attenuated miR-765 inhibition effects on TGF-ß-stimulated BPH-1 cells. In conclusion, this study provides a MIR663AHG/miR-765/FOXK1 axis modulating TGF-ß-induced epithelial proliferation and EMT, which might exert an underlying effect on BPH development and act as therapeutic targets for BPH treatment regimens.
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MicroRNAs , Hiperplasia Prostática , Masculino , Humanos , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Próstata/metabolismo , Próstata/patologia , Transição Epitelial-Mesenquimal/genética , Hiperplasia/metabolismo , Movimento Celular , Fator de Crescimento Transformador beta1/metabolismo , MicroRNAs/metabolismo , Proliferação de Células , Células Epiteliais/metabolismo , Fatores de Transcrição ForkheadRESUMO
OBJECTIVES: Renal cancer is a common malignancy of the urinary system, and the partial nephrectomy is a common surgical modality for early renal cancer. 3D printing technology can create a visual three-dimensional model by using 3D digital models of the patient's imaging data. With this model, surgeons can perform preoperative assessment to clarify the location, depth, and blood supply of the tumor, which helps to develop preoperative plans and achieve better surgical outcomes. In this study, the R.E.N.A.L scoring system was used to stratify patients with renal tumors and to explore the clinical application value of 3D printing technology in laparoscopic partial nephrectomy. METHODS: A total of 114 renal cancer patients who received laparoscopic partial nephrectomy in Xiangya Hospital from June 2019 to December 2020 were enrolled. The patients were assigned into an experimental group (n=52) and a control group (n=62) according to whether 3D printing technology was performed, and the differences in perioperative parameters between the 2 groups were compared. Thirty-nine patients were assigned into a low-complexity group (4-6 points), 32 into a moderate-complexity group (7-9 points), and 43 into a high-complexity group (10-12 points) according to R.E.N.A.L score, and the differences in perioperative parameters between the experimental group and the control group in each score group were compared. RESULTS: The experimental group had shorter operative time, renal ischemia time, and postoperative hospital stay (all P<0.05), less intraoperative blood loss (P=0.047), and smaller postoperative blood creatinine change (P=0.032) compared with the control group. In the low-complexity group, there were no statistically significant differences between the experimental group and the control group in operation time, renal ischemia time, intraoperative blood loss, postoperative blood creatinine changes, and postoperative hospital stay (all P>0.05). In the moderate- and high- complexity groups, the experimental group had shorter operative time, renal ischemia time, and postoperative hospital stay (P<0.05 or P<0.001), less intraoperative blood loss (P=0.022 and P<0.001, respectively), and smaller postoperative blood creatinine changes (P<0.05 and P<0.001, respectively) compared with the control group. CONCLUSIONS: Compared with renal tumor patients with R.E.N.A.L score<7, renal cancer patients with R.E.N.A.L score≥7 may benefit more from 3D printing assessment before undergoing partial nephrectomy.
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Neoplasias Renais , Laparoscopia , Perda Sanguínea Cirúrgica , Creatinina , Feminino , Humanos , Isquemia , Neoplasias Renais/cirurgia , Laparoscopia/métodos , Masculino , Nefrectomia/métodos , Impressão Tridimensional , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Accumulating evidences demonstrated tumor microenvironment (TME) of bladder cancer (BLCA) may play a pivotal role in modulating tumorigenesis, progression, and alteration of biological features. Currently we aimed to establish a prognostic model based on TME-related gene expression for guiding clinical management of BLCA. METHODS: We employed ESTIMATE algorithm to evaluate TME cell infiltration in BLCA. The RNA-Seq data from The Cancer Genome Atlas (TCGA) database was used to screen out differentially expressed genes (DEGs). Underlying relationship between co-expression modules and TME was investigated via Weighted gene co-expression network analysis (WGCNA). COX regression and the least absolute shrinkage and selection operator (LASSO) analysis were applied for screening prognostic hub gene and establishing a risk predictive model. BLCA specimens and adjacent tissues from patients were obtained from patients. Bladder cancer (T24, EJ-m3) and bladder uroepithelial cell line (SVHUC1) were used for genes validation. qRT-PCR was employed to validate genes mRNA level in tissues and cell lines. RESULTS: 365 BLCA samples and 19 adjacent normal samples were selected for identifying DEGs. 2141 DEGs were identified and used to construct co-expression network. Four modules (magenta, brown, yellow, purple) were regarded as TME regulatory modules through WGCNA and GO analysis. Furthermore, seven hub genes (ACAP1, ADAMTS9, TAP1, IFIT3, FBN1, FSTL1, COL6A2) were screened out to establish a risk predictive model via COX and LASSO regression. Survival analysis and ROC curve analysis indicated our predictive model had good performance on evaluating patients prognosis in different subgroup of BLCA. qRT-PCR result showed upregulation of ACAP1, IFIT3, TAP1 and downregulation of ADAMTS9, COL6A2, FSTL1,FBN1 in BLCA specimens and cell lines. CONCLUSIONS: Our study firstly integrated multiple TME-related genes to set up a risk predictive model. This model could accurately predict BLCA progression and prognosis, which offers clinical implication for risk stratification, immunotherapy drug screen and therapeutic decision.
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Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Microambiente Tumoral/genética , Neoplasias da Bexiga Urinária/mortalidade , Idoso , Estudos de Viabilidade , Feminino , Humanos , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , RNA-Seq , Curva ROC , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Análise de Sobrevida , Bexiga Urinária , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
OBJECTIVE: To investigate the mortality, operation time, cystectomy time, and complications of anterior approach laparoscopic radical cystectomy (ALRC) in Asian males in comparison with posterior approach laparoscopic radical cystectomy (PLRC). MATERIALS AND METHODS: One hundred forty-seven male patients with bladder cancer (cT2-3NxM0) in our hospital from May 2011 to January 2018 having undergone laparoscopic radical cystectomy were studied, including 68 patients in PLRC group and 79 patients in ALRC group. Baseline patient characteristics, operative and postoperative characteristics, and postoperative complications were retrospectively collected and analyzed between the two groups. RESULTS: Patients in these two groups exhibited similar baseline characteristics (p > 0.05). Compared with PLRC group, ALRC group required similar operation time (317.3 ± 40.9 vs 321.9 ± 37.5) and cystectomy time (64.8 ± 8.7 vs 65.6 ± 14.0). The ALRC group required less cystectomy time (67.8 ± 10.1 vs 77.4 ± 14.9) when patients' BMI > 24 or patients had large total tumor and blood clot volume (> 160 cm3). Also, estimated blood loss (EBL) of ALRC group was significantly less than that of PLRC group (477.8 ± 97.4 vs 550.4 ± 99.9). There existed no significant differences between the PLRC and ALRC groups in postoperative characteristics and complications. CONCLUSION: This study revealed that ALRC required less cystectomy time for patients with higher BMI and larger tumor, suggesting less blood loss and similar perioperative complications. ALRC is recommend for male patients, of which BMI > 24 or total tumor and blood clot volume > 160 cm3.
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Perda Sanguínea Cirúrgica/estatística & dados numéricos , Cistectomia/métodos , Laparoscopia/métodos , Complicações Pós-Operatórias , Neoplasias da Bexiga Urinária/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/patologiaRESUMO
PURPOSE: Enhanced recovery after surgery (ERAS) has played an important role in recovery management for radical cystectomy with ileal urinary diversion (RC-IUD). This study is to evaluate ERAS compared with the conventional recovery after surgery (CRAS) for RC-IUD. METHODS: From October 2014 and July 2016, bladder cancer patients scheduled for curative treatment from 25 centers of Chinese Bladder Cancer Consortium were randomly assigned to either ERAS or CRAS group. Primary endpoint was the 30-day complication rate. Secondary endpoints included recovery of fluid and regular diet, flatus, bowel movement, ambulation, and length of stay (LOS) postoperatively. Follow-up period was 30-day postoperatively. RESULTS: There were 144 ERAS and 145 CRAS patients. Postoperative complications occurred in 25.7 and 30.3% of the ERAS and CRAS patients with 55 complications in each group, respectively (p = 0.40). There was no significant difference between groups in major complications (p = 0.82), or type of complications (p = 0.99). The ERAS group had faster recovery of bowel movements (median 88 versus 100 h, p = 0.01), fluid diet tolerance (68 versus 96 h, p < 0.001), regular diet tolerance (125 versus 168 h, p = 0.004), and ambulation (64 versus 72 h, p = 0.047) than the CRAS group, but similar time to flatus and LOS. CONCLUSIONS: ERAS did not increase 30-day complications compared with CRAS after RC. ERAS may be better than CRAS in terms of bowel movement, tolerance of fluid and regular diet, and ambulation.
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Cistectomia , Cuidados Pós-Operatórios/métodos , Neoplasias da Bexiga Urinária/cirurgia , Derivação Urinária , China , Cistectomia/métodos , Feminino , Humanos , Íleo/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recuperação de Função FisiológicaRESUMO
OBJECTIVE: This study presents our initial experience with extraperitoneal and transperitoneal laparoscopic partial cystectomy (LPC) in the treatment of benign non-urothelial bladder tumors. METHODS: Eleven patients with benign non-urothelial bladder tumors underwent extraperitoneal or transperitoneal LPC. The five cases with tumors located on the anterior/anterolateral bladder wall received the extraperitoneal approach. The six cases with tumors located around the bladder dome or over the posterior bladder wall received the transperitoneal approach. Key perioperative parameters were recorded. RESULTS: All patients underwent laparoscopic resection smoothly without requiring a conversion to a traditional open procedure, and no patient displayed perioperative complications. Pathology showed benign non-urothelial bladder tumors with normal margins in all eleven patients, including five leiomyoma cases, three pheochromocytoma cases, two paraganglioma cases and one inflammatory fibrous histiocytoma case. Follow-up cystoscopy and imaging studies in all eleven patients (mean follow-up period 32 months) revealed neither residual nor local recurrence. CONCLUSIONS: LPC is safe and feasible in select patients with benign non-urothelial bladder tumors and yields satisfactory oncological and functional results. Extraperitoneal LPC should be preferred for lesions located on the anterior/anterolateral bladder wall, while transperitoneal LPC should be preferred for lesions around the bladder dome or over the posterior bladder wall.
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Cistectomia/métodos , Laparoscopia/métodos , Neoplasias da Bexiga Urinária/cirurgia , Adulto , Idoso , Cistectomia/efeitos adversos , Cistoscopia , Estudos de Viabilidade , Feminino , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Peritônio , Espaço Retroperitoneal , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Chemotherapeutic insensitivity and tumor cell invasiveness are major obstacles to effectively treating muscle-invasive bladder cancer (MIBC). Recent reports show that microRNAs (miRNAs) play an important role in the chemotherapeutic response and disease progression of MIBC. Therefore, here we investigated the role of miR-150 in MIBC cells in vitro. MATERIAL AND METHODS: miR-150 expression was quantified by qRT-PCR in two MIBC cell lines (5637 and T24). After successful miR-150 inhibition by transfection, MTS and transwell assays were used to assess the MIBC's cisplatin sensitivity and cell invasiveness, respectively. The TargetScan database and a luciferase reporter system were used to identify whether the programmed cell death 4 protein (PDCD4) is a direct target of miR-150 in MIBC cells. RESULTS: miR-150 expression was found to be significantly increased in both MIBC cell lines, and treatment with a miR-150 inhibitor significantly sensitized MIBC cells to cisplatin and inhibited MIBC cell invasiveness. PDCD4 was identified as a direct target of miR-150 in MIBC cells, and increased PDCD4 expression via transfection with the pLEX-PDCD4 plasmid efficiently sensitized MIBC cells to cisplatin chemotherapy and inhibited MIBC cell invasiveness. CONCLUSIONS: This study provides novel evidence that miR-150 functions as a tumor promoter in reducing chemosensitivity and promoting invasiveness of MIBC cells via targeting PDCD4. Thus, modulation of the miR-150-PDCD4 axis shows promise as a therapeutic strategy for MIBC.
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Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , MicroRNAs/fisiologia , Invasividade Neoplásica , Proteínas de Ligação a RNA/efeitos dos fármacos , Neoplasias da Bexiga Urinária/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Primers do DNA , Progressão da Doença , Humanos , Proteínas de Ligação a RNA/metabolismo , Neoplasias da Bexiga Urinária/metabolismoRESUMO
[This retracts the article DOI: 10.3892/etm.2015.2633.].
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Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an urgent need to explore combined therapies. Systematic multi-omics analysis identified S100A5 as a novel immunosuppressive target for BLCA. The expression of S100A5 in malignant cells inhibited CD8+ T cell recruitment by decreasing pro-inflammatory chemokine secretion. Furthermore, S100A5 attenuated effector T cell killing of cancer cells by inhibiting CD8+ T cell proliferation and cytotoxicity. In addition, S100A5 acted as an oncogene, thereby promoting tumor proliferation and invasion. Targeting S100A5 synergized with the efficacy of anti-PD-1 treatment by enhancing infiltration and cytotoxicity of CD8+ T cells in vivo. Clinically, there was a spatially exclusive relationship between S100A5+ tumor cells and CD8+ T cells in tissue microarrays. Moreover, S100A5 negatively correlated with immunotherapy efficacy in our real-world and several public immunotherapy cohorts. In summary, S100A5 shapes a non-inflamed tumor microenvironment in BLCA by inhibiting the secretion of pro-inflammatory chemokines and the recruitment and cytotoxicity of CD8+ T cells. Targeting S100A5 converts cold tumors into hot tumors, thus enhancing the efficacy of ICB therapy in BLCA.
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Carcinoma , Neoplasias da Bexiga Urinária , Humanos , Linfócitos T CD8-Positivos , Bexiga Urinária , Imunoterapia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Carcinoma/metabolismo , Microambiente TumoralRESUMO
Asthma is the most common chronic disease within the paediatric population. Although it is multifactorial, its onset may be linked to early-life exposures with subsequent impact on immune system development. Microbial and dietary metabolic products have been implicated in the development and exacerbation of paediatric asthma. Linoleic acid is the most common omega-6 polyunsaturated fatty acid in the Western diet. In this review, we summarise the literature regarding the involvement of linoleic acid in the development of and its impact on existing paediatric asthma. First, we summarise the existing knowledge surrounding the relationship between human microbial metabolism and allergic diseases in children. Next, we examine cellular or animal model-based mechanistic studies that investigated the impact of dietary- and microbial-derived linoleic acid metabolites on asthma. Finally, we review the literature investigating the impact of linoleic acid metabolites on the development and exacerbation of childhood asthma. While there is conflicting evidence, there is growing support for a role of linoleic acid in the onset and pathophysiology of asthma. We recommend that additional cellular, animal, and longitudinal studies are performed that target linoleic acid and its metabolites.
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Asma , Ácido Linoleico , Criança , Animais , Humanos , Asma/tratamento farmacológico , Asma/metabolismoRESUMO
OBJECTIVE: To explore the degree, mechanism and clinical significance of three-dimensional tumor microvascular architecture phenotype heterogeneity (3D-TMAPH) in non-small cell carcinoma (NSCLC). METHODS: Twenty-one samples of solitary pulmonary nodules were collected integrally. To establish two-dimensional tumor microvascular architecture phenotype (2D-TMAP) and three-dimensional tumor microvascular architecture phenotype (3D-TMAP), five layers of each nodule were selected and embedded in paraffin. Test indices included the expressions of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), EphB4, ephfinB2 and microvascular density marked by anti-CD34 (CD34-MVD). The degrees of 3D-TMAPH were evaluated by the coefficient of variation and extend of heterogeneity. Spearman rank correlation analysis was used to investigate the relationships between 2D-TMAP, 3D-TMAP and clinicopathological features. RESULTS: 3D-TMAPH showed that 2D-TMAP heterogeneity was expressed in the tissues of NSCLC. The heterogeneities in the malignant nodules were significantly higher than those in the active inflammatory nodules and tubercular nodules. In addition, different degrees of heterogeneity of CD34-MVD and PCNA were found in NSCLC tissues. The coefficients of variation of CD34- MVD and PCNA were positively related to the degree of differentiation (all P<0.05), but not related to the P-TNM stages, histological type or lymphatic metastasis (all P>0.05). The level of heterogeneity of various expression indexes (ephrinB2, EphB4, VEGF) in NSCLC tissues were inconsistent, but there were no significant differences in heterogeneity in NSCLC tissues with different histological types (P>0.05). CONCLUSION: 3D-TMAPH exists widely in the microenvironment during the genesis and development of NSCLC and has a significant impact on its biological complexity.
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Capilares/ultraestrutura , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Efrina-B2/metabolismo , Neoplasias Pulmonares/irrigação sanguínea , Neovascularização Patológica , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Fenótipo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Although intravesical gemcitabine (GEM) chemotherapy (IGC) can effectively reduce the recurrence risk of non-muscle invasive bladder cancer (NMIBC), the development of GEM resistance may occur and result in cancer recurrence and disease progression. Herein, a label-free proteomics approach was used to characterize the proteomic profiles of primary/post-IGC recurrent NMIBC. A total of 218 proteins were found to be differentially expressed in paired primary and post-IGC recurrent NMIBC. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that multiple signaling pathways including "focal adhesion" were highly enriched in recurrent NMIBC. Niban apoptosis regulator 1 (NIBAN1) was identified as the top upregulated protein in recurrent NMIBC. Highly increased NIBAN1 expression was observed in a number of GEM-resistant cancer cell lines and in post-IGC recurrent NMIBC specimens. Manipulation of NIBAN1 expression affected the chemosensitivity to GEM in bladder cancer cell models. Moreover, NIBAN1 also regulated focal adhesion/focal adhesion kinase (FAK) signaling activation in bladder cancer cell lines. Highly elevated FAK (pY397) expression was observed in post-IGC recurrent NMIBC specimens, which was positively correlated with NIBAN1 expression. Knockdown of FAK markedly attenuated GEM resistance in GEM-resistant bladder cancer cells. In vivo studies demonstrated that knockdown of NIBAN1 disrupted FAK signaling and sensitized GEM-resistant bladder cancer cells to GEM treatment. Our findings suggest that NIBAN1 might regulate FAK signaling activation to promote GEM resistance in bladder cancer. Targeting NIBAN1/FAK signaling may help sensitize bladder cancer cells to GEM treatment.
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Regulator of G protein signaling 20 (RGS20) plays an important role in regulating neuronal G protein-coupled receptor signaling; however, its expression and oncogenic function in penile cancer (PC) remains unclear. Here, we observed high RGS20 expression in PC tissues compared to normal/adjacent penile tissues, which was closely associated with tumor stage, nodal status, and pelvic metastasis in our PC cohort. The cellular functional analysis of RGS20 revealed that manipulation of the RGS20 expression markedly affected cell viability, BrdU incorporation, soft agar clonogenesis, caspase-3 activity, and cell migration/invasion in PC cell models. Moreover, RGS20 could interact with PI3K p85α subunit and regulate PI3K/AKT signaling activation in PC cell lines. Knockdown of the PI3K p85α or p110α subunit attenuated cell viability, BrdU incorporation, soft agar clonogenesis, and cell migration/invasion in PC cell lines. In contrast, the overexpression of constitutively activated PI3K p110α mutant restored cell proliferation and cell migration/invasion caused by RGS20 depletion in PC cells. Consistent with the in vitro findings, RGS20 depletion attenuated PI3K/AKT signaling activation and suppressed tumor growth in a murine xenograft model. Importantly, the high RGS20 expression was associated with PI3K/AKT signaling activation and unfavorable progression-free/overall survival, highlighting the clinical relevance of RGS20/PI3K/AKT signaling in PC. In conclusion, the aberrant RGS20 expression may serve as a diagnostic and prognostic marker for PC. RGS20 may promote PC progression through modulating PI3K/AKT signaling activation, which may assist with the development of RGS20-targeting therapeutics in the future.
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PURPOSE: Serum biomarkers are valuable tools to predict the prognosis of anticancer therapies. This study aimed to evaluate the impact of serum interleukin-6 (IL-6) level on the clinical outcome of intravesical gemcitabine (GEM) therapy in non-muscle-invasive bladder cancer (NMIBC). METHODS: This retrospective study enrolled 71 patients initially diagnosed with T1 NMIBC who underwent intravesical GEM therapy between 2017 and 2019. The expression of IL-6 gene was examined by real-time PCR. Serum IL-6 level was determined by enzyme-linked immunosorbent assay (ELISA). The cell viability after gemcitabine treatment was measured by CCK-8 assay. The optimal serum IL-6 cutoff values for recurrence prediction were calculated using receiver-operating characteristic curve analysis with reference to cancer recurrence. Recurrence-free survival was compared by the log-rank test. Univariate and multivariate Cox regression analysis was conducted to identify the prognostic factors influencing recurrence-free survival after treatment with intravesical GEM. RESULTS: Increased expression and secretion of IL-6 were observed in GEM-resistant sublines compared with parental bladder cancer cell lines. Serum IL-6 level rendered a sensitivity of 82.6% and a specificity of 77.1% to correlate with the cancer recurrence after intravesical GEM. Patients with a high serum IL-6 level exhibited shorter recurrence-free survival after intravesical GEM. Moreover, serum IL-6 level in our NMIBC cohort was significantly associated with clinicopathological characteristics, such as tumor diameter, multifocality, concomitant CIS, and grade. Serum IL-6 level was an independent prognostic factor for recurrence-free survival in NMIBC patients treated with intravesical GEM. CONCLUSION: Given that it was significantly associated with clinical outcome of intravesical GEM therapy, serum IL-6 level might be used as a potential prognostic biomarker for intravesical GEM in T1 NMIBC.
Assuntos
Neoplasias da Bexiga Urinária , Administração Intravesical , Desoxicitidina/análogos & derivados , Humanos , Interleucina-6 , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estudos Retrospectivos , GencitabinaRESUMO
Background: Epithelial mesenchymal transition (EMT) is closely related to the occurrence, development, metastasis and antitumor immunity of tumors. However, comprehensive studies correlating EMT and prognosis, tumor microenvironment (TME) and molecular subtypes of bladder cancer (BLCA) are lacking. Methods: TCGA-BLCA was chosen as our training cohort, while Xiangya cohort, GSE13507, GSE48075 were selected as our validation cohorts. Prognostic genes were screened out using univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) algorithm. Then we developed an EMT risk score based on these prognostic genes and systematically correlated the risk score with prognosis, TME and molecular subtypes of BLCA. Results: Based on EMT related genes, we developed two different EMT patterns, named EMT cluster 1 and cluster 2, and found that cluster 2 showed a worse prognosis and an inflammatory TME phenotype. For personalized prognosis and TME phenotypes predicting, we developed and validated an EMT-based risk score by 7 candidate genes (ANXA10, CNTN1, FAM180A, FN1, IGFL2, KANK4 and TOX3). Patients with high EMT risk scores had lower overall survival (OS) with high predictive accuracy both in the training cohort and validation cohort. In addition, we comprehensively correlated the EMT risk score with TME and molecular subtype, and found that high EMT risk score suggested higher levels of immune cell infiltration and more inclined to present the basal molecular subtype. It was noteworthy that the same results also appeared in the validation of Xiangya cohort. Conclusions: EMT related genes play an important role in tumor progression and immunity in BLCA. Our EMT risk score could accurately predict prognosis and immunophenotype of a single patient, which could guide more effective precision medical strategies.
Assuntos
Neoplasias da Bexiga Urinária , Transição Epitelial-Mesenquimal/genética , Humanos , Prognóstico , Fatores de Risco , Microambiente Tumoral/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
The test of four rubber concrete filled steel tube (RuCFST) members, one concrete filled steel tube (CFST) member and one empty member were conducted under pure bending. The main parameters were the shear span ratio (λ) from 3 to 5, and the rubber replacing ratio (r) from 10% to 20%. The bending moment-strain curves, the bending moment-deflection curves and the bending moment-curvature curves were obtained. The failure modes of core rubber concrete were analyzed. The failure mode of RuCFST members was bending failure from the results. The cracks of rubber concrete were distributed evenly and sparsely, and the filling of rubber in core concrete prevented the development of cracks. The shear span ratio has little effect on the behavior of the tested specimens. While the rubber replacing ratio had little effect on the bending moment capacity, but had some influence on the bending stiffness of the tested specimens. After filling in rubber concrete, the bending moment capacity and the bending stiffness can be improved compared with the empty steel tube specimen.
RESUMO
Background: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumor derived from the adrenal cortex. Because of its highly aggressive nature, the prognosis of patients with adrenocortical carcinoma is not impressive. Hypoxia exists in the vast majority of solid tumors and contributes to invasion, metastasis, and drug resistance. This study aimed to reveal the role of hypoxia in Adrenocortical carcinoma and develop a hypoxia risk score (HRS) for Adrenocortical carcinoma prognostic prediction. Methods: Hypoxia-related genes were obtained from the Molecular Signatures Database. The training cohorts of patients with adrenocortical carcinoma were downloaded from The Cancer Genome Atlas, while another three validation cohorts with comprehensive survival data were collected from the Gene Expression Omnibus. In addition, we constructed a hypoxia classifier using a random survival forest model. Moreover, we explored the relationship between the hypoxia risk score and immunophenotype in adrenocortical carcinoma to evaluate the efficacy of immune check inhibitors (ICI) therapy and prognosis of patients. Results: HRS and tumor stage were identified as independent prognostic factors. HRS was negatively correlated with immune cycle activity, immune cell infiltration, and the T cell inflammatory score. Therefore, we considered the low hypoxia risk score group as the inflammatory immunophenotype, whereas the high HRS group was a non-inflammatory immunophenotype. In addition, the HRS was negatively related to the expression of common immune checkpoint molecules such as PD-L1, CD200, CTLA-4, and TIGIT, suggesting that patients with a lower hypoxia risk score respond better to immunotherapy. Conclusion: We developed and validated a novel hypoxia risk score to predict the immunophenotype and response of patients with adrenocortical carcinoma to immune check inhibitors therapy. These findings not only provide fresh prognostic indicators for adrenocortical carcinoma but also offer several promising treatment targets for this disease.