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BACKGROUND: Cholangiocarcinoma is the most common malignancy of the biliary tree and has a poor prognosis. Adenocarcinoma is the most common pathological type of cholangiocarcinomas, but rare squamous, adenosquamous, and mucinous variants have been reported without adequate clinical data. CASE SUMMARY: This report describes a rare case of primary squamous cell carcinoma (SCC) of the intrahepatic bile duct. The patient was admitted with a tumor in the hepatic caudate lobe with no obvious clinical symptoms. Examination revealed hepatitis B surface antigen positivity, a slight increase in alfa-fetoprotein to 16.34 ng/mL, and an irregular slightly heterogeneous enhancing lesion in the hepatic caudate lobe, which was initially thought to be hepatocellular carcinoma. Laparoscopic resection was performed, and the final pathology suggested a rare primary SCC of the intrahepatic bile duct. Immunohistochemistry indicated positivity for villin, partial positivity for p63, and negativity for hepatocyte, CK7, CK8, CK19, and CK20. The Ki-67 index was approximately 60%. The patient received six cycles of Tegio chemotherapy. A new lesion was detected in the liver after 15 months. The surgery was performed, and the patient was followed-up at a local hospital. To date, no new lesions have been observed. CONCLUSION: Surgery is the first choice for resectable lesions, and combined chemotherapy based on pathology is essential for increasing overall survival.
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In the realm of large-area trauma flap transplantation, averting ischaemic necrosis emerges as a pivotal concern. Several key mechanisms, including the promotion of angiogenesis, the inhibition of oxidative stress, the suppression of cell death, and the mitigation of inflammation, are crucial for enhancing skin flap survival. Apoptotic bodies (ABs), arising from cell apoptosis, have recently emerged as significant contributors to these functions. This study engineered three-dimensional (3D)-ABs using tissue-like mouse adipose-derived stem cells (mADSCs) cultured in a 3D environment to compare their superior biological effects against 2D-ABs in bolstering skin flap survival. The findings reveal that 3D-ABs (85.74 ± 4.51) % outperform 2D-ABs (76.48 ± 5.04) % in enhancing the survival rate of ischaemic skin flaps (60.45 ± 8.95) % (all p < 0.05). Mechanistically, they stimulated angiogenesis, mitigated oxidative stress, suppressed apoptosis, and facilitated the transition of macrophages from M1 to M2 polarization (all p < 0.05). A comparative analysis of microRNA (miRNA) profiles in 3D- and 2D-ABs identified several specific miRNAs (miR-423-5p-up, miR30b-5p-down, etc.) with pertinent roles. In summary, ABs derived from mADSCs cultured in a 3D spheroid-like arrangement exhibit heightened biological activity compared to those from 2D-cultured mADSCs and are more effective in promoting ischaemic skin flap survival. These effects are attributed to their influence on specific miRNAs.
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Tecido Adiposo , Apoptose , Técnicas de Cultura de Células , Isquemia , Células-Tronco , Células Cultivadas , Humanos , Animais , Camundongos , Células-Tronco/citologia , Células-Tronco/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Células/métodos , Separação Celular/métodos , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Isquemia/genética , Isquemia/patologia , Hipóxia Celular , Sobrevivência Celular , MicroRNAs/genética , Estresse Oxidativo , Neovascularização Patológica , Perfilação da Expressão GênicaRESUMO
Background: Ensuring the survival of the distal end of a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention of programmed cell death is a potential strategy for inhibiting ischaemic flap necrosis. The activation of stimulator of interferon genes (STING) pathway promotes inflammation and leads to cell death. The epidermal growth factor family member neuregulin-1 (NRG1) reduces cell death by activating the protein kinase B (AKT) signalling pathway. Moreover, AKT signalling negatively regulates STING activity. We aimed to verify the efficacy of NRG1 injection in protecting against flap necrosis. Additionally, we investigated whether NRG1 effectively enhances ischemic flap survival by inhibiting pyroptosis and necroptosis through STING suppression. Methods: A random-pattern skin flap model was generated on the backs of C57BL/6 mice. The skin flap survival area was determined. The blood supply and vascular network of the flap was assessed by laser Doppler blood flow analysis. Cluster of differentiation 34 immunohistochemistry (IHC) and haematoxylin and eosin (H&E) staining of the flap sections revealed microvessels. Transcriptome sequencing analysis revealed the mechanism by which NRG1 promotes the survival of ischaemic flaps. The levels of angiogenesis, oxidative stress, necroptosis, pyroptosis and indicators associated with signalling pathways in flaps were examined by IHC, immunofluorescence and Western blotting. Packaging adeno-associated virus (AAV) was used to activate STING in flaps. Results: NRG1 promoted the survival of ischaemic flaps. An increased subcutaneous vascular network and neovascularization were found in ischaemic flaps after the application of NRG1. Transcriptomic gene ontology enrichment analysis and protein level detection indicated that necroptosis, pyroptosis and STING activity were reduced in the NRG1 group. The phosphorylation of AKT and forkhead box O3a (FOXO3a) were increased after NRG1 treatment. The increased expression of STING in flaps induced by AAV reversed the therapeutic effect of NRG1. The ability of NRG1 to phosphorylate AKT-FOXO3a, inhibit STING and promote flap survival was abolished after the application of the AKT inhibitor MK2206. Conclusions: NRG1 inhibits pyroptosis and necroptosis by activating the AKT-FOXO3a signalling pathway to suppress STING activation and promote ischaemic flap survival.
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Preventing and treating avascular necrosis at the distal end of the flaps are critical to surgery success, but current treatments are not ideal. A recent study shows that apoptotic bodies (ABs) generated near the site of apoptosis can be taken up and promote cell proliferation. The study reveals that ABs derived from fibroblast-like cells in the subcutaneous connective tissue (FSCT cells) of skin flaps promoted ischaemic flap survival. It is also found that ABs inhibited cell death and oxidative stress and promoted M1-to-M2 polarization in macrophages. Transcriptome sequencing and protein level testing demonstrated that ABs promoted ischaemic flap survival in endothelial cells and macrophages by inhibiting ferroptosis via the KEAP1-Nrf2 axis. Furthermore, microRNA (miR) sequencing data and in vitro and in vivo experiments demonstrated that ABs inhibited KEAP1 by delivering miR-339-5p to exert therapeutic effects. In conclusion, FSCT cell-derived ABs inhibited ferroptosis, promoted the macrophage M1-to-M2 transition via the miR-339-5p/KEAP1/Nrf2 axis and promoted ischaemic flap survival. These results provide a potential therapeutic strategy to promote ischaemic flap survival by administering ABs.
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Ferroptose , Fibroblastos , Proteína 1 Associada a ECH Semelhante a Kelch , MicroRNAs , Fator 2 Relacionado a NF-E2 , Retalhos Cirúrgicos , Animais , Camundongos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Ferroptose/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Fibroblastos/metabolismo , Modelos Animais de Doenças , Isquemia/metabolismo , Isquemia/genética , Masculino , Apoptose/genética , Tecido Conjuntivo/metabolismo , Transdução de Sinais/genéticaRESUMO
Avascular necrosis frequently occurs as a complication following surgery involving the distal perforator flap. Dihydrocapsaicin (DHC) can protect tissue from ischemia-reperfusion (I/R) injury, but its specific role in multizone perforator flaps remains unclear. In this study, the prospective target of DHC in the context of I/R injury was predicted using network pharmacology analysis. Flap viability was determined through survival area analysis, laser Doppler blood flow, angiograms, and histological examination. The expressions of angiogenesis, apoptosis, NLR family pyrin domain containing 3 (NLRP3) inflammasome, oxidative stress, and molecules related to cyclic guanosine monophosphate (GMP)-adenosine monophosphate synthase (cGAS)-interferon gene stimulant (STING) pathway were assessed using western blotting, immunofluorescence, TUNEL staining, and dihydroethidium (DHE) staining. Our finding revealed that DHC promoted the perforator flap survival, which involves the cGAS-STING pathway, oxidative stress, NLRP3 inflammasome, apoptosis, and angiogenesis. DHC induced oxidative stress resistance and suppressed the NLRP3 inflammasome, preventing apoptosis in vascular endothelial cells. Through regulation of STING pathway, DHC controlled oxidative stress in endothelial cells and NLRP3 levels in ischemic flaps. However, activation of the cGAS-STING pathway led to the accumulation of reactive oxygen species (ROS) and NLRP3 inflammasome, thereby diminishing the protective role of DHC. DHC enhanced the survival of multidomain perforator flaps by suppressing the cGAS-STING pathway, oxidative stress, and the formation of NLRP3 inflammasome. These findings unveil a potentially novel mechanism with clinical significance for promoting the survival of multidomain perforator flaps.
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Apoptose , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Retalho Perfurante , Traumatismo por Reperfusão , Animais , Humanos , Masculino , Camundongos , Apoptose/efeitos dos fármacos , Inflamassomos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controleRESUMO
OBJECTIVE: This study aimed to investigate the clinicopathological features and prognostic indicators of alveolar soft part sarcoma (ASPS). METHODS: The characteristics of 26 ASPS patients diagnosed at our hospital between January 2011 and January 2019 were retrospectively analysed. RESULTS: The data for 12 male and 14 female patients, with a median age of 27.5 years, were assessed. The clinical symptoms mainly included painless enlarged masses in deep soft tissues. ASPS had a characteristic pathological morphology. Twenty-four patients were positive for TFE3, and TFE3 gene rearrangement was detected in 12 patients. Among the 26 patients who completed follow-up, 14 had metastasis, 1 had local recurrence, and 7 died. Kaplan-Meier survival analysis revealed that prognosis was significantly correlated with sex, tumour size and metastasis (P < 0.05). Multivariate Cox regression analysis revealed that sex and metastasis were independent prognostic risk factors for patients with ASPS (P < 0.05). CONCLUSION: ASPS is a rare soft tissue sarcoma of unknown origin that occurs in young people, has a slow but metastatic course, and is associated with a poor 5-year survival rate among patients with metastasis. ASPS has character TFE3 protein and gene expression, and the diagnosis is relatively specific. The diagnosis requires comprehensive analysis of clinical history, histological morphology, and immunohistochemistry.
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Sarcoma Alveolar de Partes Moles , Humanos , Masculino , Feminino , Adolescente , Adulto , Estudos Retrospectivos , Sarcoma Alveolar de Partes Moles/diagnóstico , Sarcoma Alveolar de Partes Moles/genética , Sarcoma Alveolar de Partes Moles/patologia , Prognóstico , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de RiscoRESUMO
BACKGROUND AND PURPOSE: Ischaemia-reperfusion (I/R) injury is a major contributor to skin flap necrosis, which presents a challenge in achieving satisfactory therapeutic outcomes. Previous studies showed that cathelicidin-BF (BF-30) protects tissues from I/R injury. In this investigation, BF-30 was synthesized and its role and mechanism in promoting survival of I/R-injured skin flaps explored. EXPERIMENTAL APPROACH: Survival rate analysis and laser Doppler blood flow analysis were used to evaluate I/R-injured flap viability. Western blotting, immunofluorescence, TdT-mediated dUTP nick end labelling (TUNEL) and dihydroethidium were utilized to examine the levels of apoptosis, pyroptosis, oxidative stress, transcription factor EB (TFEB)-mediated autophagy and molecules related to the adenosine 5'-monophosphate-activated protein kinase (AMPK)-transient receptor potential mucolipin 1 (TRPML1)-calcineurin signalling pathway. KEY RESULTS: The outcomes revealed that BF-30 enhanced I/R-injured island skin flap viability. Autophagy, oxidative stress, pyroptosis and apoptosis were related to the BF-30 capability to enhance I/R-injured flap survival. Improved autophagy flux and tolerance to oxidative stress promoted the inhibition of apoptosis and pyroptosis in vascular endothelial cells. Activation of TFEB increased autophagy and inhibited endothelial cell oxidative stress in I/R-injured flaps. A reduction in TFEB level led to a loss of the protective effect of BF-30, by reducing autophagy flux and increasing the accumulation of reactive oxygen species (ROS) in endothelial cells. Additionally, BF-30 modulated TFEB activity via the AMPK-TRPML1-calcineurin signalling pathway. CONCLUSION AND IMPLICATIONS: BF-30 promotes I/R-injured skin flap survival by TFEB-mediated up-regulation of autophagy and inhibition of oxidative stress, which may have possible clinical applications.
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Piroptose , Traumatismo por Reperfusão , Humanos , Espécies Reativas de Oxigênio/metabolismo , Catelicidinas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Células Endoteliais/metabolismo , Calcineurina/farmacologia , Autofagia , Traumatismo por Reperfusão/metabolismo , Fatores de TranscriçãoRESUMO
Extracellular vesicles (EVs) are membrane-enclosed nanovesicles secreted by cells into the extracellular space and contain functional biomolecules, e.g. signaling receptors, bioactive lipids, nucleic acids, and proteins, which can serve as biomarkers. Neurons and glial cells secrete EVs, contributing to various physiological and pathological aspects of brain diseases. EVs confer their role in the bidirectional crosstalk between the central nervous system (CNS) and the periphery owing to their distinctive ability to cross the unique blood-brain barrier (BBB). Thus, EVs in the blood, cerebrospinal fluid (CSF), and urine can be intriguing biomarkers, enabling the minimally invasive diagnosis of CNS diseases. Although there has been an enormous interest in evaluating EVs as promising biomarkers, the lack of ultra-sensitive approaches for isolating and detecting brain-derived EVs (BDEVs) has hindered the development of efficient biomarkers. This review presents the recent salient findings of exosomal biomarkers, focusing on brain disorders. We summarize highly sensitive sensors for EV detection and state-of-the-art methods for single EV detection. Finally, the prospect of developing advanced EV analysis approaches for the non-invasive diagnosis of brain diseases is presented.
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Encefalopatias , Doenças do Sistema Nervoso Central , Vesículas Extracelulares , Humanos , Encéfalo/metabolismo , Vesículas Extracelulares/metabolismo , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/metabolismo , Encefalopatias/diagnóstico , BiomarcadoresRESUMO
Breast cancer has become the malignant disease with the highest morbidity and mortality among female cancer patients. The prognosis of metastatic breast cancer is very poor, and the therapeutic effects still need to be improved. The molecular mechanism of breast cancer has not been fully clarified. Bioinformatics analysis was used to find the differentially expressed gene that affects the occurrence and development of breast cancer. Furthermore, scratch assays, Transwell assays, immunofluorescence, and Western blotting were used to determine the biological behavior of breast cancer cells affected by DEP domain-containing protein 1B (DEPDC1B). The molecular mechanism was investigated by mass spectrometry analysis, coimmunoprecipitation, and ubiquitin assays. Here, we found that DEPDC1B was highly expressed in breast cancer cells and tissues and was associated with lower overall survival (OS) in patients. We found that DEPDC1B interference significantly inhibited tumor invasion and migration in vitro and tumor metastasis in vivo. Mechanistically, DEPDC1B was first shown to activate the wnt/ß-catenin signaling pathway as an oncogene in breast cancer cells. In addition, we also confirmed the interaction between DEPDC1B, ubiquitin-specific protease 5 (USP5), and ß-catenin. Then, we found that DEPDC1B mediates the deubiquitination of ß-catenin via USP5, which promotes cell invasion and migration. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be considered a potential therapeutic target for breast cancer.NEW & NOTEWORTHY By using bioinformatics analysis and the experimental techniques of cell biology and molecular biology, we found that DEP domain-containing protein 1B (DEPDC1B) can promote the invasion and migration of breast cancer cells and that DEPDC1B mediates the deubiquitination of ß-catenin by ubiquitin-specific protease 5 (USP5), thus activating the wnt/ß-catenin pathway. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be used as a potential therapeutic target for breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , beta Catenina/genética , Via de Sinalização Wnt , Proteases Específicas de Ubiquitina/genética , Proteínas Ativadoras de GTPase , Melanoma Maligno CutâneoRESUMO
Iron is an essential element required for all organisms. Iron response regulator (Irr) is a crucial transcriptional regulator and can affect the growth and iron uptake of Brucella. The growth rate of Brucella melitensis M5-90 irr mutant was significantly lower than that of B. melitensis M5-90 under normal or iron-sufficient conditions, however, the growth rate of the B. melitensis M5-90 irr mutant was significantly higher than that of B. melitensis M5-90 under iron-limited conditions. In addition, irr mutation significantly reduced iron uptake under iron-limited conditions. Previous studies suggested that the Irr protein has multiple target genes in the Brucella genome that are involved in iron metabolism. Therefore, in the present study, a Dap-seq approach was used to investigate the other iron metabolism genes that are also regulated by the Irr protein in Brucella. A total of seven genes were identified as target genes for Irr in this study and the expression levels of these seven genes was identified using qRT-PCR. The electrophoretic mobility shift assay confirmed that six out of the seven genes, namely rirA (BME_RS13665), membrane protein (BME_RS01725), hypothetical protein (BME_RS09560), ftrA (BME_RS14525), cation-transporting P-type ATPase (zntA) (BME_RS10660), and 2Fe-2S binding protein (BME_RS13655), interact with the Irr protein. Furthermore, the iron utilization and growth assay experiments confirmed that rirA was involve in iron metabolism and growth of Brucella. In summary, our results identified six genes regulated by the Irr protein that may participate in iron metabolism, and the rirA was identified as a regulon of Irr and it also plays a role in iron metabolism of Brucella. Collectively, these results provide valuable insights for the exploration of Brucella iron metabolism.
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Brucella melitensis , Brucelose , Humanos , Ferro/metabolismo , Brucella melitensis/genética , Brucella abortus/genética , Sítios de Ligação , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão GênicaRESUMO
Xinjiang pastoral area is the second largest pastoral area in China, accounting for 26.8% of the available grassland area in the country, and the geographical advantage of cattle breeding industry is very obvious. Bovine viral diarrhea virus (BVDV) has always been one of the important viral diseases that have plagued the development of cattle farming industry in the world. As one of the main pastoral areas of China's cattle farming industry, the Xinjiang pastoral area has also been deeply affected. In this study, 6,153 bovine serum samples were collected from 18 large-scale cattle farms in 13 cities in Xinjiang. The antibodies and antigens of 6,153 and 588 serum samples were detected by serological detection methods, respectively. Ten serum samples, which were antigen-positive by ELISA, were randomly selected for RT-PCR detection, sequencing, and phylogenetic analysis of suspected HoBi-like Pestivirus (HoBiPeV) strains. The results showed that the positive rates of BVDV antibodies and antigens were 53.68% (3,303/6,153) and 6.12% (36/588), respectively. One of the 10 randomly selected seropositive samples was infected with the HoBiPeV strain. HoBiPeV, also referred to as BVDV-3, is an emerging atypical Pestivirus that occurs in cattle and small ruminants, and its clinical signs are similar to those of BVDV infection. Based on the whole genome of the BVDV-3 reference strain (JS12/01) on the GenBank, the homology of the detected strain was 96.02%. The whole genome nucleotide sequence was submitted to the GenBank database, and the gene accession number was obtained: OP210314. The whole genome of isolate OP210314 was 12.239 nucleotides and contained a 5'-UTR of 340 nucleotides, a 3'-UTR of 199 nucleotides, and a large open reading frame (ORF) encoding a polyprotein consisting of 3,899 amino acids. In conclusion, the prevalence rate of BVDV infection in Xinjiang dairy cows is high, and the genetic diversity is increasing. This study successfully identified and isolated HoBiPeV in Xinjiang for the first time, posing a potential threat to the cattle industry in Xinjiang.
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Osteosarcoma (OS) is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity. Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities. However, the underlying molecular mechanism of these discrepancies remains unclear. The potential role of mechanotransduction in tumorigenicity is of particular interest. To this end, we tested the tumorigenicity and anoikis resistance of OS cell lines both in vitro and in vivo. We utilized a sphere culture model, a soft agar assay, and soft and rigid hydrogel surface culture models to investigate the function of rigidity sensing in the tumorigenicity of OS cells. Additionally, we quantified the expression of sensor proteins, including four kinases and seven cytoskeletal proteins, in OS cell lines. The upstream core transcription factors of rigidity-sensing proteins were further investigated. We detected anoikis resistance in transformed OS cells. The mechanosensing function of transformed OS cells was also impaired, with general downregulation of rigidity-sensing components. We identified toggling between normal and transformed growth based on the expression pattern of rigidity-sensing proteins in OS cells. We further uncovered a novel TP53 mutation (R156P) in transformed OS cells, which acquired gain of function to inhibit rigidity sensing, thus sustaining transformed growth. Our findings suggest a fundamental role of rigidity-sensing components in OS tumorigenicity as mechanotransduction elements through which cells can sense their physical microenvironment. In addition, the gain of function of mutant TP53 appears to serve as an executor for such malignant programs.
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OBJECTIVES: Pseudomyogenic hemangioendothelioma (PHE) is a rare intermediate hemangioendothelioma. This article aims to study the clinicopathological features of PHE. METHODS: We collected the clinicopathological features of 10 new PHE, and examined their molecular pathological features by fluorescence in situ hybridization. In addition, we summarized and analyzed the pathological data of 189 reported cases. RESULTS: The case group consisted of six men and four women aged 12-83 years (median: 41 years). Five instances occurred in the limbs, three in the head and neck, and two in the trunk. Tumor tissues were composed of spindle cells and round or polygonal epithelioid cells, which were either arranged in sheets or interwoven, along with areas of transitional morphology. Scattered or patchy stromal neutrophil infiltration was observed. Tumor cells had abundant cytoplasm, and some contained vacuoles. The nuclei had mild to moderate atypia, with visible nucleoli, and mitosis was rare. PHE tissues diffusely expressed CD31 and ERG, but not CD34, Desmin, SOX-10, HHV8 or S100, while some samples expressed CKpan, FLI-1 and EMA. INI-1 stain is retained. The proliferation index of Ki-67 is 10-35%. Seven samples were detected by fluorescence in situ hybridization, six of which had breakages in FosB proto-oncogene (AP-1 transcription factor subunit). Two patients experienced recurrence; however, no metastasis or death occurred. CONCLUSIONS: PHE is a rare soft tissue vascular tumor, which has biologically borderline malignant potential, local recurrence, little metastasis, and good overall survival and prognosis. Immunomarkers and molecular detection are valuable for diagnosis.
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Hemangioendotelioma Epitelioide , Hemangioendotelioma , Hemangioma , Lesões Pré-Cancerosas , Neoplasias de Tecidos Moles , Feminino , Humanos , Masculino , Biomarcadores Tumorais/genética , Hemangioendotelioma/diagnóstico , Hemangioendotelioma/patologia , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Hibridização in Situ Fluorescente , Neoplasias de Tecidos Moles/patologia , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou maisRESUMO
Background: Immunotherapy has become the new standard of care for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC), and PD-L1 is a widely used biomarker for immunotherapeutic response. However, PD-L1 expression in most cancer patients is low, and alternative biomarkers used to screen the population benefiting from immunotherapy are still being explored. Tumor microenvironment (TME), especially tumor immune-infiltrating cells, regulates the body's immunity, affects the tumor growth, and is expected to be a promising biomarker for immunotherapy. Purpose: This article mainly discussed how the immune-infiltrating cell patterns impacted immunity, thereby affecting HNSCC patients' prognosis. Method: The immune-infiltrating cell profile was generated by the CIBERSORT algorithm based on the transcriptomic data of HNSCC. Consensus clustering was used to divide groups with different immune cell infiltration patterns. Differentially expressed genes (DEGs) obtained from the high and low immune cell infiltration (ICI) groups were subjected to Kaplan-Meier and univariate Cox analysis. Significant prognosis-related DEGs were involved in the construction of a prognostic signature using multivariate Cox analysis. Results: In our study, 408 DEGs were obtained from high- and low-ICI groups, and 59 of them were significantly associated with overall survival (OS). Stepwise multivariate Cox analysis developed a 16-gene prognostic signature, which could distinguish favorable and poor prognosis of HNSCC patients. An ROC curve and nomogram verified the sensitivity and accuracy of the prognostic signature. The AUC values for 1 year, 2 years, and 3 years were 0.712, 0.703, and 0.700, respectively. TCGA-HNSCC cohort, GSE65858 cohort, and an independent GSE41613 cohort proved a similar prognostic significance. Notably, the prognostic signature distinguished the expression of promising immune inhibitory receptors (IRs) well and could predict the response to immunotherapy. Conclusion: We established a tumor immune cell infiltration (TICI)-based 16-gene signature, which could distinguish patients with different prognosis and help predict the response to immunotherapy.
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BACKGROUND: Anal squamous cell carcinoma (ASCC) is the main subtype of anal cancer and has great heterogeneity in prognosis. We aimed to construct a nomogram for predicting their 1-, 3-, and 5-year overall survival (OS) rates. METHODS: Patients with ASCC, enrolled between January 1, 2010 and December 31, 2017, were identified from the SEER database. They were divided into a training group and a validation group in a ratio of 7:3. Univariate and multivariate Cox analyses were used to identify the prognostic factors for OS. Then a prognostic nomogram was established and validated by Harrell consistency index (C-index), area under the curve (AUC) of the receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). RESULTS: We identified 761 patients in training group and 326 patients in validation group. Four prognostic factors including age, sex, AJCC stage, and radiotherapy were identified and integrated to construct a prognostic nomogram. The C-index and AUC values proved the model's effectiveness and calibration plots manifested its excellent discrimination. Furthermore, in comparison to the AJCC stage, the C-index, AUC, and DCA proved the nomogram to be of good predictive value. Finally, we constructed a risk stratification model for dividing patients into low-risk, medium-risk, and high-risk groups, and there were obvious differences in OS. CONCLUSIONS: A prognostic nomogram was firstly established for predicting the survival probability of ASCC patients and helping clinicians improve their risk management.
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Neoplasias do Ânus/mortalidade , Carcinoma de Células Escamosas/mortalidade , Nomogramas , Idoso , Neoplasias do Ânus/patologia , Neoplasias do Ânus/terapia , Área Sob a Curva , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Curva ROC , Programa de SEER , Taxa de SobrevidaRESUMO
Background: DNA methylation played essential roles in regulating gene expression. The impact of DNA methylation status on the occurrence and development of cancers has been well demonstrated. However, little is known about its prognostic role in breast cancer (BC). Materials: The Illumina Human Methylation450 array (450k array) data of BC was downloaded from the UCSC xena database. Transcriptomic data of BC was downloaded from the Cancer Genome Atlas (TCGA) database. Firstly, we used univariate and multivariate Cox regression analysis to screen out independent prognostic CpGs, and then we identified methylation-associated prognosis subgroups by consensus clustering. Next, a methylation prognostic model was developed using multivariate Cox analysis and was validated with the Illumina Human Methylation27 array (27k array) dataset of BC. We then screened out differentially expressed genes (DEGs) between methylation high-risk and low-risk groups and constructed a methylation-based gene prognostic signature. Further, we validated the gene signature with three subgroups of the TCGA-BRCA dataset and an external dataset GSE146558 from the Gene Expression Omnibus (GEO) database. Results: We established a methylation prognostic signature and a methylation-based gene prognostic signature, and there was a close positive correlation between them. The gene prognostic signature involved six genes: IRF2, KCNJ11, ZDHHC9, LRP11, PCMT1, and TMEM70. We verified their expression in mRNA and protein levels in BC. Both methylation and methylation-based gene prognostic signatures showed good prognostic stratification ability. The AUC values of 3-years, 5-years overall survival (OS) were 0.737, 0.744 in the methylation signature and 0.725, 0.715 in the gene signature, respectively. In the validation groups, high-risk patients were confirmed to have poorer OS. The AUC values of 3 years were 0.757, 0.735, 0.733 in the three subgroups of TCGA dataset and 0.635 in GSE146558 dataset. Conclusion: This study revealed the DNA methylation landscape and established promising methylation and methylation-based gene prognostic signatures that could serve as potential prognostic biomarkers and therapeutic targets.
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BACKGROUND: Perivascular epithelioid cell tumor (PEComa) is an uncommon tumor of mesenchymal origin. Cases of PEComa in the liver are extremely rare. AIM: To analyze the clinicopathological features and treatment of hepatic PEComa and to evaluate the prognosis after different treatments. METHODS: Clinical and pathological data of 26 patients with hepatic PEComa were collected. All cases were analyzed by immunohistochemistry and clinical follow-up. RESULTS: This study included 17 females and 9 males, with a median age of 50 years. Lesions were located in the left hepatic lobe in 13 cases, in the right lobe in 11, and in the caudate lobe in 2. The median tumor diameter was 6.5 cm. Light microscopy revealed that the tumor cells were mainly composed of epithelioid cells. The cytoplasm contained heterogeneous eosinophilic granules. There were thick-walled blood vessels, around which tumor cells were radially arranged. Immunohistochemical analysis of pigment-derived and myogenic markers in PEComas revealed that 25 cases were HMB45 (+), 23 were Melan-A (+), and 22 SMA (+). TFE3 and Desmin were negative in all cases. All the fluorescence in situ hybridization samples were negative for TFE3 gene break-apart probe. Tumor tissues were collected by extended hepatic lobe resection or simple hepatic tumor resection as the main treatments. Median follow-up was 62.5 mo. None of the patients had metastasis or recurrence, and there were no deaths due to the disease. CONCLUSION: Hepatic PEComa highly expresses melanin and smooth muscle markers, and generally exhibits an inert biological behavior. The prognosis after extended hepatic lobe resection and simple hepatic tumor resection is semblable.
Assuntos
Recidiva Local de Neoplasia , Neoplasias de Células Epitelioides Perivasculares , Gerenciamento Clínico , Feminino , Humanos , Hibridização in Situ Fluorescente , Fígado , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Epitelioides Perivasculares/cirurgia , PrognósticoRESUMO
PURPOSE: As a non-classical ligand of Wnt, the abnormal regulation of Wnt5a contributes to the progression of malignant tumors; however, its effects differ depending on tumor type. Here, we evaluated the expression and significance of Wnt5a in endometrioid adenocarcinoma and its relationship with epithelial-mesenchymal transition (EMT)-related proteins. PATIENTS AND METHODS: Immunohistochemical streptavidin-peroxidase method and reverse transcription polymerase chain reaction (RT-PCR) method were used to analyze the expression and correlation of Wnt5a, and EMT-related protein ß-catenin, E-cadherin and enhancer of zeste homolog 2 (EZH2) in endometrial cancer tissues and cell samples of each group. RESULTS: The expression of Wnt5a and E-cadherin decreased in the following order, normal endometrium > atypical hyperplasia endometrium > endometrioid adenocarcinoma. In contrast, the expression of ß-catenin and EZH2 increased gradually. Moreover, Wnt5a expression was associated with the degree of tissue differentiation, International Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastasis (all P<0.05). Wnt5a expression was also negatively correlated with ß-catenin and EZH2 expression and positively correlated with E-cadherin expression. RT-PCR results further indicated that E-cadherin mRNA expression was upregulated in a Wnt5a-overexpressing Ishikawa cell line compared to cells transfected with an empty vector or negative control cells (P<0.01). Furthermore, the expression of EZH2 and ß-catenin mRNA was downregulated in overexpressing cells compared to empty vector and negative control cells (P<0.01). CONCLUSION: Wnt5a may elicit a suppressive effect on endometrioid adenocarcinoma by inhibiting EMT. This study provides a theoretical basis for the pathological diagnosis and targeted therapy of endometrioid adenocarcinoma and extends our understanding of the Wnt5a signaling pathway.
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BACKGROUND: Growing evidence has suggested that enhancer RNAs (eRNAs), a set of long non-coding RNAs (lncRNAs) that were derived from active enhancer regions, play critical roles in regulating gene expression in human cancers. Nevertheless potential functions of eRNAs in esophageal cancer ESCA have not yet been expounded. Here, this study aimed to explore key prognostic eRNAs in ESCA. METHODS: LncRNAs that were transcribed from active enhancer regions were analyzed utilizing the PreSTIGE algorithm, followed by prediction of their target genes. Based on the ESCA RNA-seq data from the TANRIC database, overall survival (OS)-related eRNAs were determined. The correlation between AC007255.1 expression and various clinical traits of ESCA was calculated. Functional enrichment analysis was presented based on its co-expressed genes. Based on the TIMER database, we analyzed correlations between AC007255.1 expression and immune infiltration levels. qRT-PCR was utilized to validate the expression of AC007255.1 and PRR15 in ESCA and normal tissues. RESULTS: Totally, 2,695 lncRNAs were transcribed from active enhancer regions. Among them, 33 were significantly related to OS. AC007255.1 was a key eRNA. PRR15 was a target gene of AC007255.1 (correlation coefficient r = 0.936). Patients with high AC007255.1 expression indicated poor OS time. There were significant correlations between AC007255.1 expression and clinical characteristics like pathological TNM, grade and stage. AC007255.1 was closely related to tight junction and neutrophil activation involved in immune response. Moreover, AC007255.1 expression was related to the infiltration levels of B cell, dendritic cell and neutrophil. qRT-PCR results confirmed that AC007255.1 and PRR15 were both up-regulated in ESCA tissues, and there was a positive correlation between the two. CONCLUSION: Our findings identified a novel immune-related eRNA AC007255.1 in ESCA, which could be a promising prognostic factor for ESCA.
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Colorectal cancer (CRC) is one of the most common tumors worldwide and is associated with high mortality. Here we performed bioinformatics analysis, which we validated using immunohistochemistry in order to search for hub genes that might serve as biomarkers or therapeutic targets in CRC. Based on data from The Cancer Genome Atlas (TCGA), we identified 4832 genes differentially expressed between CRC and normal samples (1562 up-regulated and 3270 down-regulated in CRC). Gene ontology (GO) analysis showed that up-regulated genes were enriched mainly in organelle fission, cell cycle regulation, and DNA replication; down-regulated genes were enriched primarily in the regulation of ion transmembrane transport and ion homeostasis. Weighted gene co-expression network analysis (WGCNA) identified eight gene modules that were associated with clinical characteristics of CRC patients, including brown and blue modules that were associated with cancer onset. Analysis of the latter two hub modules revealed the following six hub genes: adhesion G protein-coupled receptor B3 (BAI3, also known as ADGRB3), cyclin F (CCNF), cytoskeleton-associated protein 2 like (CKAP2L), diaphanous-related formin 3 (DIAPH3), oxysterol binding protein-like 3 (OSBPL3), and RERG-like protein (RERGL). Expression levels of these hub genes were associated with prognosis, based on Kaplan-Meier survival analysis of data from the Gene Expression Profiling Interactive Analysis database. Immunohistochemistry of CRC tumor tissues confirmed that OSBPL3 is up-regulated in CRC. Our findings suggest that CCNF, DIAPH3, OSBPL3, and RERGL may be useful as therapeutic targets against CRC. BAI3 and CKAP2L may be novel biomarkers of the disease.