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Ribosome profiling and mass spectrometry have revealed thousands of previously unannotated small and alternative open reading frames (sm/alt-ORFs) that are translated into micro/alt-proteins in mammalian cells. However, their prevalence across human tissues and biological roles remains largely undefined. The placenta is an ideal model for identifying unannotated microproteins and alt-proteins due to its considerable protein diversity that is required to sustain fetal development during pregnancy. Here, we profiled unannotated microproteins and alt-proteins in human placental tissues from preeclampsia patients or healthy individuals by proteomics, identified 52 unannotated microproteins or alt-proteins, and demonstrated that five microproteins can be translated from overexpression constructs in a heterologous cell line, although several are unstable. We further demonstrated that one microprotein, XRCC6P1, associates with translation initiation factor eIF3 and negatively regulates translation when exogenously overexpressed. Thus, we revealed a hidden sm/alt-ORF-encoded proteome in the human placenta, which may advance the mechanism studies for placenta development as well as placental disorders such as preeclampsia.
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Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis.
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Carcinoma de Pulmón de Células no Pequeñas , Diterpenos , Resistencia a Antineoplásicos , Compuestos Epoxi , Proteínas Hedgehog , Factor Nuclear 1-alfa del Hepatocito , Neoplasias Pulmonares , Paclitaxel , Fenantrenos , Compuestos Epoxi/farmacología , Compuestos Epoxi/uso terapéutico , Humanos , Fenantrenos/farmacología , Fenantrenos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Diterpenos/farmacología , Diterpenos/uso terapéutico , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Hedgehog/metabolismo , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Animales , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Ratones Desnudos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Ratones , Ratones Endogámicos BALB C , Células A549RESUMEN
BACKGROUND: To present an unusual case of abnormal LCA expression and CD43 in SCLC and to review the reported literature to avoid potential diagnostic pitfalls. CASE PRESENTATION: A 73-year-old male patient suffered from persistent back pain for more than one month. MRI revealed a compression fracture of the L1-L5 vertebra. A CT scan revealed multiple nodules and masses at the left root of the neck, lung hilum and mediastinum, and multiple areas of bony destruction of the ribs. Histology of the tumor revealed that small and round cells were arranged in nests with areas of necrosis. The tumor cells were round to ovoid with scant cytoplasm and indistinct cell borders. The nuclear chromatin was finely granular, and the nucleoli were absent or inconspicuous. Immunohistochemically, the tumor cells were positive for cytokeratin, TTF-1, POU2F3, LCA, and CD43. CONCLUSION: This report highlights a potential diagnostic pitfall in the diagnosis of SCLC, urges pathologists to exercise caution in cases of LCA and CD43 positivity and illustrates the need for further immunohistochemical studies to avoid misdiagnosis.
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Leucosialina , Neoplasias Pulmonares , Humanos , Masculino , Anciano , Leucosialina/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Tomografía Computarizada por Rayos X , Inmunohistoquímica , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: Colorectal cancer (CRC) is a common malignant tumor, and this study aims to explore the role and the regulatory mechanism of carboxypeptidase A6 (CPA6) in CRC cells. METHODS: Specific shRNA targeting CPA6 mRNA was transfected into NCM460 and HT29 cells to down-regulate CPA expression, and expression plasmid was transfected into HCT116 cells to exogenously overexpress CPA6. The dual luciferase assay was used to detect the direct binding of miR-96-3p to CPA6 3'UTR. Phosphorylation and activation of Akt were detected using Western blot. Cells were treated with miR-96-3p mimics, Akt inhibitor (MK-2206) or agonist (SC79) for rescue experiments. The cell functions were evaluated using CCK-8, clone formation, transwell, and Western blot assays. Xenograft tumor assay was also used to analyze the effect of altered CPA6 expression on tumor growth. RESULTS: Knockdown of CPA6 promoted the proliferation, clone formation, migration, and invasion of NCM460 and HT29 cells in vitro, and the tumor growth of nude mouse xenograft tumor in vivo. Moreover, over-expression of CPA6 significantly inhibited the malignant proliferation and invasion of HCT116 cells in vitro, and the tumor growth of xenograft tumor in vivo. Furthermore, miR-96-3p could directly regulate CPA6 expression by targeting its 3'UTR, and miR-96-3p mimics rescued the inhibitory effects of CPA6 overexpression on the malignant proliferation and invasion of CRC cells. Finally, CPA6 knockdown enhanced Akt/mTOR phosphorylation and activation, while CPA6 overexpression inhibited Akt/mTOR activation. The regulatory effect of CPA6 on Akt/mTOR signaling was naturally regulated by miR-96-3p. Akt inhibitor or agonist rescued the effects of CPA6 knockdown or overexpression on proliferation and EMT of colon cancer cells. CONCLUSION: CPA6 has a significant tumor suppressive effect on CRC by inhibiting the activation of Akt/mTOR signaling, and miR-96-3p negatively regulates the expression of CPA6.
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Neoplasias Colorrectales , MicroARNs , Animales , Ratones , Humanos , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Regiones no Traducidas 3' , Movimiento Celular/genética , Neoplasias Colorrectales/patología , Proliferación Celular , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/metabolismo , Carboxipeptidasas/genética , Carboxipeptidasas/metabolismo , Carboxipeptidasas/farmacología , Regulación Neoplásica de la Expresión GénicaRESUMEN
OBJECTIVE: Most endoscopists routinely perform moderate or deep sedation for esophagogastroduodenoscopy (EGD). Considering that there is no consensus on the optimal sedation depth and it varies from country to country, our study aims to compare the effectiveness, cost and safety of these two sedation methods in the Chinese population. METHODS: This quasi-experimental study included a total of 556 eligible patients from July 2020 to June 2021, and they entered the moderate sedation group or deep sedation group based on their choices. Baseline information, scores of Patient Satisfaction with Sedation Instrument (PSSI) and Clinician Satisfaction with Sedation Instrument (CSSI), examination time, sedation time, recovery time, expenses before medicare reimbursement, hypoxaemia and hypotension were compared between the two groups. Propensity Score Matching (PSM) analysis was conducted to balance the confounding factors. RESULTS: After PSM, 470 patients were involved in the analysis, with 235 for each group. The moderate sedation was clearly superior to the deep sedation group in terms of PSSI score (98.00 ± 0.94 vs. 97.29 ± 1.26), CSSI score (98.00 ± 0.78 vs. 97.67 ± 1.30), sedation time (11.90 ± 2.04 min vs. 13.21 ± 2.75 min), recovery time (25.40 ± 3.77 min vs. 28.0 ± 4.85 min), expenses (433.04 ± 0.00 Yuan vs. 789.85 ± 0.21 Yuan), with all p < .001. Examination time was not significantly different between the two groups (p = .124). In addition, the moderate sedation group had a lower occurrence rate of hypoxaemia (0.36% vs. 3.27%, p = .010) and hypotension (17.44% vs. 44.00%, p < .001) compared to the deep sedation group. CONCLUSIONS: Moderate sedation presented better effectiveness and safety and lower cost, and thereby it should be recommended as a widely used sedation method in clinical practice in China. Trial registration: This trial was registered on http://www.chictr.org.cn/index.aspx (ChiCTR2000038050).
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Sedación Profunda , Hipotensión , Propofol , Anciano , Sedación Consciente/métodos , Análisis Costo-Beneficio , Sedación Profunda/efectos adversos , Sedación Profunda/métodos , Endoscopía del Sistema Digestivo/efectos adversos , Endoscopía del Sistema Digestivo/métodos , Humanos , Hipnóticos y Sedantes/efectos adversos , Hipotensión/etiología , Hipoxia/etiología , Medicare , Estados UnidosRESUMEN
BACKGROUND: Jumonji AT-rich interactive domain 1B(JARID1B) has been shown to be upregulated in many human cancers and plays a critical role in the development of cancers cells. Nevertheless, its functional role in colorectal cancer (CRC) progression is not fully understood. METHODS: Herein, JARID1B expression levels were detected in clinical CRC samples by western blotting and qRT-PCR. DLD-1 cells with JARID1B knockdown or overexpression by stably transfected plasmids were used in vitro and in vivo study. Colony formation, 5-ethynyl-20-deoxyuridine (EdU) and Real Time Cellular Analysis (RTCA) assays were used to detect cell proliferation and growth. Transcriptome and CHIP assays were used to examine the molecular biology changes and molecular interaction in these cells. Nude mice was utilized to study the correlation of JARID1B and tumor growth in vivo. RESULTS: Here, we first observed that JARID1B was significantly upregulated in CRC tissue compared to adjacent normal tissues. In CRC patients, JARID1B high expression was positively relation with poor overall survival. Multivariate analyses revealed that high JARID1B expression was an independent predictive marker for the poor prognosis of CRC. In addition, we found that JARID1B promoted CRC cells proliferation by Wnt/ß-catenin signaling pathway. Further studies demonstrated CDX2 as a downstream target of JARID1B, and our data demonstrated that CDX2 is crucial for JARID1B -mediated Wnt/ß-catenin signaling pathway. Mechanistically, we demonstrated that JARID1B regulated CDX2 expression through demethylation of H3K4me3. CONCLUSIONS: CDX2 inhibited by JARID1B-derived H3K4me3 methylation promoted cells proliferation of CRC via Wnt/ß-catenin signaling pathway. Therefore, our studies provided a novel insight into the role of JARID1B in CRC cells proliferation and potential new molecular target for treating CRC. Video abstract.
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Factor de Transcripción CDX2/metabolismo , Neoplasias Colorrectales/patología , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Vía de Señalización Wnt , Animales , Factor de Transcripción CDX2/genética , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Progresión de la Enfermedad , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Lisina/metabolismo , Masculino , Metilación , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Análisis Multivariante , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , Proteínas Represoras/genética , Análisis de Supervivencia , Regulación hacia Arriba/genéticaRESUMEN
Background: DNMT3A is the main molecule responsible for DNA methylation in cells. DNMT3A affects the progression of inflammation, degenerative diseases, and malignant tumors, and exhibits significant aberrantly expression in tumor tissues. Methods: Transcriptome data and relevant clinical information were downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) datasets. Differential expression analysis and prognostic analysis were conducted based on above statistics. We constructed a clinical prognostic model and identified DNMT3A as an independent prognostic factor to accurately predict patient prognosis. Differential gene enrichment analysis revealed that DNMT3A affects the progression of glioma through multiple pathways, among which the tumor necrosis factor-α (TNF-α)/nuclear factor-kappa B (NF-κB) pathway shows a strong correlation. Immunological analysis also revealed a certain correlation between DNMT3A and tumor immunity. We demonstrated through gene editing that DNMT3A can affect the release of TNF-α in cells, thereby affecting the progression of glioma. Functional experiments have also demonstrated that DNMT3A plays a crucial role in tumors. Results: RNA-sequencing and survival analyses of lower-grade glioma (LGG) patients in TCGA, CGGA, and GEO cohorts showed that high DNMT3A expression correlated with poor prognosis of LGG patients. Univariate and multivariate Cox regression analyses showed that DNMT3A expression was an independent prognostic indicator in LGG. The prognosis prediction nomogram with age, World Health Organization (WHO) grading, and DNMT3A expression showed reliable performance in predicting the 1-, 3-, and 5-year overall survival (OS) of LGG patients. Functional enrichment analysis, gene set enrichment analysis (GSEA), and ESTIMATE algorithm analyses showed that DNMT3A expression was associated with the tumor infiltration of immune cells and predicted response to immunotherapy in two immunotherapy cohorts of pan-cancer patients. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of DNMT3A in the LGG cell lines suppressed proliferation, migration, and invasion of LGG cells by downregulating the TNF-α/NF-κB signaling pathway. Conclusions: Our data showed that DNMT3A was a potential prognostic biomarker in glioma. DNMT3A promoted proliferation and malignancy of LGG cells through the TNF-α/NF-κB signaling pathway. DNMT3A is a promising therapeutic target for treating patients with LGG.
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POU class 2 homeobox 3 (POU2F3)-positive small cell bladder carcinoma (SCBC) is an extremely rare entity, and its clinicopathologic features have not been fully described. Here, we investigated the clinicopathologic features of 4 cases of POU2F3-positive small cell bladder carcinoma (SCBC) and reviewed the literature. We collected 12 cases of SCBC from our departmental archives and detected the expression of POU2F3 by immunohistochemical (IHC) staining. Selected cases with or without POU2F3 expression were subjected to gene expression analysis between two different groups using DESeq2 software. We identified 4 POU2F3-positive SCBC patients, 2 males and 2 females, with a mean age of 77 years. Three patients had hematuria, and 1 patient had dysuria. Radiologic findings showed a bladder mass. Pathologic diagnosis showed that 3 cases were pure SCBC and 1 was mixed urothelial cancer (UC). Histopathologically, four POU2F3-positive SCBC tumors were composed of small round cells with sparse cytoplasm, the nuclei were salt-and-pepper-like or finely granular. Tumor cells showed characteristic cytoplasmic staining with punctate positive signals for cytokeratin. Syn and CD56 were diffusely positive in all the 4 patients. CgA was positive in only one patient. POU2F3-positive SCBC showed higher expression levels of POU2F3, HMGA2 and PLCG2 genes by RNA-Seq. Our data showed the specific clinicopathologic features of 4 rare POU2F3-positive SCBC cases, and the distinct molecular feature was observed between POU2F3-positive and negative SCBC in the limited number of cases.
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Biomarcadores de Tumor , Carcinoma de Células Pequeñas , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Masculino , Femenino , Anciano , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Anciano de 80 o más Años , Persona de Mediana Edad , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/análisisRESUMEN
Lacking effective therapeutic targets heavily restricts the improvement of clinical prognosis for patients diagnosed with esophageal squamous cell carcinoma (ESCC). Ubiquitin Specific Peptidase 21 (USP21) is dysregulated in plenty of human cancers, however, its potential function and relevant molecular mechanisms in ESCC malignant progression as well as its value in clinical translation remain largely unknown. Here, in vitro and in vivo experiments revealed that aberrant upregulation of USP21 accelerated the proliferation and metastasis of ESCC in a deubiquitinase-dependent manner. Mechanistically, we found that USP21 binds to, deubiquitinates, and stabilizes the G3BP Stress Granule Assembly Factor 1 (G3BP1) protein, which is required for USP21-mediated ESCC progression. Further molecular studies demonstrated that the USP21/G3BP1 axis played a tumor-promoting role in ESCC progression by activating the Wnt/ß-Catenin signaling pathway. Additionally, disulfiram (DSF), an inhibitor against USP21 deubiquitylation activity, markedly abolished the USP21-mediated stability of G3BP1 protein and significantly displayed an anti-tumor effect on USP21-driving ESCC progression. Finally, the regulatory axis of USP21/G3BP1 was demonstrated to be aberrantly activated in ESCC tumor tissues and closely associated with advanced clinical stages and unfavorable prognoses, which provides a promising therapeutic strategy targeting USP21/G3BP1 axis for ESCC patients.
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Dysregulation of MOF (also known as MYST1, KAT8), a highly conserved H4K16 acetyltransferase, plays important roles in human cancers. However, its expression and function in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we report that MOF is highly expressed in ESCC tumors and predicts a worse prognosis. Depletion of MOF in ESCC significantly impedes tumor growth and metastasis both in vitro and in vivo, whereas ectopic expression of MOF but not catalytically inactive mutant (MOF-E350Q) promotes ESCC progression, suggesting that MOF acetyltransferase activity is crucial for its oncogenic activity. Further analysis reveals that USP10, a deubiquitinase highly expressed in ESCC, binds to and deubiquitinates MOF at lysine 410, which protects it from proteosome-dependent protein degradation. MOF stabilization by USP10 promotes H4K16ac enrichment in the ANXA2 promoter to stimulate ANXA2 transcription in a JUN-dependent manner, which subsequently activates Wnt/ß-Catenin signaling to facilitate ESCC progression. Our findings highlight a novel USP10/MOF/ANXA2 axis as a promising therapeutic target for ESCC.
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Anexina A2 , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Vía de Señalización Wnt/genética , Neoplasias Esofágicas/patología , Proliferación Celular/genética , Acetiltransferasas/metabolismo , Epigénesis Genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Movimiento Celular , Histona Acetiltransferasas/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Anexina A2/metabolismoRESUMEN
The aim of this study was to examine the effect of non-pharmacological staged interventions on fatigue and dyspnoea in patients with chronic obstructive pulmonary disease. A randomized controlled trial was conducted with 64 patients in a tertiary hospital in China from 2010 to 2011. Patients were randomly assigned to the control group (n = 32), who received routine care, and the intervention group (n = 32), who received additional non-pharmacological staged interventions. The Multidimensional Fatigue Inventory and the five-grade Medical Research Council dyspnoea scale were used to collect data at baseline and after 6 weeks. Compared with the control group, patients in the intervention group had significantly lower scores on general fatigue (P < 0.001), physical fatigue (P < 0.001), reduced activity (P < 0.001) and reduced motivation (P = 0.03) and had better relief of dyspnoea (P = 0.02). Our study showed that non-pharmacological staged interventions were effective in relieving fatigue and dyspnoea in patients with chronic obstructive pulmonary disease.
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Disnea , Fatiga , Enfermedad Pulmonar Obstructiva Crónica/terapia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatologíaRESUMEN
ETS-related gene (ERG) is the member of ETS-family of transcription factors and is commonly expressed in Ewing sarcoma. Recently, we found that ERG can also be expressed in lymphoblastic lymphoma. The aim of this article is to explore the expression patterns of ERG in T-lymphoblastic lymphoma, and to evaluate its diagnostic value for differentiating T-lymphoblastic lymphoma and nonneoplastic T-precursor cells in thymoma via immunohistochemistry. In this study, we explored the expression pattern of ERG in T-lymphoblastic lymphoma and thymoma specimens via immunohistochemistry. Sixteen T-lymphoblastic lymphoma and 18 thymoma specimens were evaluated for the expression of ERG. Our findings showed that ERG was expressed in 10 of the 16 (63%) T-lymphoblastic lymphoma specimens, and in only 1 of the 18 (6%) thymoma specimens. The positive and negative predictive value of ERG in T-lymphoblastic lymphoma was 91% and 74%, respectively. ERG is a helpful marker for the diagnosis of T-lymphoblastic lymphoma and is a promising new method to differentiate T-lymphoblastic lymphoma and the nonneoplastic T-precursor cells in thymoma.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Timoma , Neoplasias del Timo , Humanos , Timoma/diagnóstico , Timoma/patología , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Inmunohistoquímica , Regulador Transcripcional ERGRESUMEN
BACKGROUND: Penile cancer is a rare malignancy with a poor prognosis, even with various treatment options. Considering the little progress in the study of the pathogenesis and treatment of penile cancer because of the lack of models that mimic the biological properties of the tumor, we have developed a patient-derived xenograft (PDX) model and paired hydrogel-embedded histoculture drug sensitivity test (HDST) to screen for drugs that can inhibit tumors. The increased expression of XPO1, as a key nuclear export protein involved in the transport of various tumor suppressors and cell cycle regulatory proteins, is associated with the prognosis of a variety of tumors [World J Uroly 27(2):141-150, 2009]. Selinexor is an inhibitor of XPO1, which can treat cancers, such as multiple myeloma, gastric cancer, triple-negative breast cancer, and non-small cell carcinoma [Transl Androl Urol 6(5):785-790, 2017; OncoTargets Therapy 13:6405-6416, 2020]. However, whether XPO1 inhibition has a role in penile cancer remains unknown. Therefore, this article used the PDX and HDST models to investigate whether the inhibition of XPO1 has an effect on penile cancer and its underlying mechanism. METHODS: We used penile cancer tumor tissues to construct a PDX model of penile cancer and paired PDXE model and confirmed the consistency of PDX tumor tissues in source patients. Then, we assessed the ability of Selinexor to inhibit penile cancer tissues in vivo using a PDX model and in vitro by HDST. We also examined the potential mechanism of XPO1 action on penile cancer by IHC and TUNEL. Finally, we assessed the safety of the drug treatment by H&E and biochemical blood analysis. RESULTS: Result showed that the penile cancer PDX model and patient penile cancer tissues were clinically consistent in morphological characteristics and protein expression. In addition, Selinexor could inhibit tumor growth in PDX models and HDST. We found that P53, P21 expression was upregulated; Cyclin D1 expression was downregulated, and apoptosis of tumor cells was increased in the Selinexor-treated PDX model. Moreover, it had no significant effect on liver, kidney, and cardiac function. CONCLUSION: The PDX model of penile cancer was a powerful tool for penile cancer research and new drug development. It showed that Selinexor can effectively inhibit penile cancer in vitro and in vivo. In addition, XPO1 may affect P53, P21, and Cyclin D1 expression to regulate the growth and apoptosis of penile carcinoma.
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Carcinoma , Neoplasias del Pene , Masculino , Animales , Humanos , Ciclina D1/metabolismo , Carioferinas/genética , Carioferinas/metabolismo , Neoplasias del Pene/tratamiento farmacológico , Hidrogeles , Xenoinjertos , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Transporte Activo de Núcleo Celular , Hidrazinas/farmacología , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Primary pelvis and spine osteosarcoma (PSOS) is a specific type of osteosarcoma that is difficult to treat and has a poor prognosis. In recent years, the research on osteosarcoma has been increasing, but there have been few studies on PSOS; in particular, there have been a lack of analyses with a large sample size. This study aimed to construct and validate a model to predict the overall survival (OS) of PSOS patients, as currently there are no tools available for assessing their prognosis. METHODS: Data including demographic information, clinical characteristics, and follow-up information on patients with PSOS were collected from the Surveillance, Epidemiology, and End Results (SEER) database, as well as from the Spine Tumor Center of Changzheng Hospital. Variable selection was achieved through a backward procedure based on the Akaike Information Criterion (AIC). Prognostic factors were identified by univariate and multivariate Cox analysis. A nomogram was further constructed for the estimation of 1-, 3-, and 5-year OS. Calibration plots, the concordance index (C-index), and the receiver operating characteristic (ROC) were used to evaluate the prediction model. RESULTS: In total, 83 PSOS patients and 90 PSOS patients were separately collected from the SEER database and Changzheng Hospital. In the SEER cohort, liver metastasis, lung metastasis, and chemotherapy were recognized as independent prognostic factors for OS (p < 0.05) and were incorporated to construct the initial nomogram. However, the initial nomogram showed poor predictive accuracy in internal and external validation. Then, we shifted our focus to the Changzheng data. Lung metastasis involving segments, Eastern Cooperative Oncology Group (ECOG) performance score, alkaline phosphatase (ALP) level, and en bloc resection were ultimately identified as independent prognostic factors for OS (p < 0.05) and were further incorporated to construct the current nomogram, of which the bias-corrected C-index was 0.834 (0.824-0.856). The areas under the ROC curves (AUCs) of the current nomogram regarding 1-, 3-, and 5-year OS probabilities were 0.93, 0.96, and 0.92, respectively. CONCLUSION: We have developed a predictive model with satisfactory performance and clinical practicability, enabling effective prediction of the OS of PSOS patients and aiding clinicians in decision-making.
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BACKGROUND: Endometriosis is a common benign gynecological disease that causes dysmenorrhea in women of childbearing age. Malignant tumors derived from endometriosis are rarely reported and are found in only 1% of all patients with endometriosis. Here, we report a well-differentiated squamous cell carcinoma (SCC) caused by squamous metaplasia of endometriosis that co-occurred in the uterus and ovaries. CASE SUMMARY: A 57-year-old postmenopausal woman had a 6-month history of irregular uterine bleeding. The uterus and adnexa were examined by computed tomography, and there were two solid cystic masses in the pelvis and right adnexa. Histological findings of surgical specimens showed well-differentiated SCC arising from squamous metaplasia of ectopic endometrial glands in the uterus and ovaries. The patient received chemotherapy after surgery and was followed up for 3 mo without metastasis. CONCLUSION: The continuity between ectopic endometrial glands and SCC supports that SCC originates from ectopic endometrial glands with metaplasia towards squamous epithelium.
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[This corrects the article DOI: 10.3389/fimmu.2022.956982.].
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CD99 is a 32-kDa transmembrane glycoprotein that is encoded by the MIC2 gene. Our study was carried out to examine the role of CD99 in tumor progression of classical Hodgkin lymphoma (cHL). Here, we showed that lowly expressed CD99 protein in cHL cell lines and primary cHL cases correlates with the deficient expression of the positive regulatory domain 1 (PRDM1/BLIMP1). In addition, cHL cell lines showed high levels of miR-9 expression. We determined that the upregulation of CD99 induced expression of transcription factor PRDM1, a master regulator of plasma-cell differentiation, which is also a target for miR-9-mediated downregulation. Indeed, inhibition of miR-9 also triggered upregulation of PRDM1 expression. Furthermore, overexpression of CD99 resulted in changed growth features and reorganization of actin cytoskeleton. As upregulation of CD99 led to a decrease in cHL diagnosis marker CD30 and CD15 and an increase in plasma-cell differentiation marker CD38 and the restoration of B-cell makers PAX5, CD79α and CD19, we suggest that downregulated CD99 leads to the prevention of plasma-cell differentiation in Hodgkin/Reed-Sternberg (H/RS) cells. Furthermore, these data indicate that CD99 may control miR-9 expression, which directly targets PRDM1. Altogether, these results reveal a CD99-miR-9-PRDM1 molecule axis in lymphomagenesis of cHL and suggest that upregulation of CD99 in H/RS cells induces terminal B-cell differentiation, which may provide a novel therapeutic strategies for cHL.
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Antígenos CD/fisiología , Moléculas de Adhesión Celular/fisiología , Diferenciación Celular/fisiología , Enfermedad de Hodgkin/patología , MicroARNs/fisiología , Células de Reed-Sternberg/fisiología , Proteínas Represoras/fisiología , Regulación hacia Arriba/fisiología , Antígeno 12E7 , Secuencia de Bases , Western Blotting , Línea Celular Tumoral , Cartilla de ADN , Citometría de Flujo , Humanos , Separación Inmunomagnética , Hibridación in Situ , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Células de Reed-Sternberg/citología , Proteínas Represoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
An increasing body of evidence shows that macrophages play an important role in the pathogenesis of ulcerative colitis (UC). Macrophage polarization and changes in related signaling pathways are reported to have a protective effect on intestinal inflammation. The well-known Chinese medicine Wumeiwan (WMW) has been used to treat diarrhea, one of the main symptoms of colitis, for more than 2,000 years. Increasing evidence shows that WMW can inhibit intestinal inflammation and repair damaged intestinal mucosa, but its effector mechanisms are unknown. Therefore, we studied the prophylactic effects of WMW in dextran sulfate sodium (DSS)-induced UC and its effects on macrophage mechanisms and polarization. The results show that colitis was significantly alleviated in mice in the WMW group, and the secretion and expression of pro-inflammatory factors TNF-α, IL-1, and IL-6 were inhibited in the serum and colonic tissues of mice with WMW-treated colitis, whereas anti-inflammatory factors IL-10, Arg-1, and TGF-ß1 were increased. Subsequent studies found that WMW could inhibit M1 polarization and promote M2 polarization in colonic macrophages in DSS-induced colitis mice. Network pharmacology was used to predict potential targets and pathways, and further studies confirmed the related targets The results showed that WMW gradually inhibits the activation of the P38MAPK and NF-κB signaling pathways and further activates the STAT6 signaling pathway. In summary, WMW interferes with the p38MAPK, NF-κB and STAT6 signaling pathways to regulate M1/M2 polarization in macrophages, thereby protecting mice against DSS-induced colitis.
RESUMEN
Background: The risk of gastrointestinal stromal tumor (GIST) in combination with other primary malignancies is high, which occurs before and after the diagnosis of GIST. Primary pulmonary T-cell lymphoma is a rare type of non-Hodgkin lymphoma. Case presentation: We report a 53-year-old male patient who was admitted to our hospital with fever, cough, and expectoration for 2 weeks. Chest computed tomography (CT) showed a cavitary mass in the left lower lobe with multiple nodules in the upper lobes of both lungs. The patient had a history of surgery for small intestinal stromal tumors and was treated with oral imatinib after surgery. Lung biopsy was diagnosed as lymphomatoid granulomatosis, tending to grade 3. The pathological diagnosis was corrected by surgery and genetic testing for lung non-Hodgkin CD8-positive cytotoxic T-cell lymphoma with Epstein-Barr virus (EBV) infection in some cells. After multiple chemotherapies, the CT scan showed a better improvement than before. The patient is still under follow-up, and no tumor recurrence has been found. Conclusion: Patients with a history of GIST should be monitored for other malignancies. The clinical symptoms and imaging examinations of primary pulmonary T-cell lymphoma are not characteristic, and the definite diagnosis still depends on pathological examination. The patient was treated with the CHOP chemotherapy regimen after the operation, the curative effect was good.
RESUMEN
Gastric mucosal injury is the initial stage of the occurrence and development of gastric diseases. Oxidative stress and ferroptosis caused by the imbalance of redox and iron dynamics in gastric mucosal epithelial cells are present throughout the occurrence and development of gastric mucosal injury. Therefore, the inhibition of oxidative stress and ferroptosis is a potential target for the treatment of the gastric mucosal injury. Xiaojianzhong decoction (XJZ), which consists of six Chinese herbal medicines and extracts, is used for the treatment of diseases related to gastrointestinal mucosal injury; however, its specific mechanism of action has yet to be clarified. In this study, we clarified the protective effect of XJZ on gastric mucosa and revealed its underlying mechanism. We established a gastric mucosal injury model using aspirin and administered XJZ. Furthermore, we systematically evaluated the mucosal injury and examined the expression of genes related to oxidative stress, ferroptosis, and inflammation. The study found that XJZ significantly counteracted aspirin-induced gastric mucosal injury and inhibited oxidative stress and ferroptosis in mice. Upon examining SQSTM1/p62(p62)/Kelch-like ECH-associated protein 1 (Keap1)/Nuclear Factor erythroid 2-Related Factor 2 (Nrf2), a well-known signaling pathway involved in the regulation of oxidative stress and ferroptosis, we found that its activation was significantly inhibited by aspirin treatment and that this signaling pathway was activated after XJZ intervention. Our study suggests that XJZ may inhibit aspirin induced oxidative stress and ferroptosis via the p62/Keap1/Nrf2 signaling pathway, thereby attenuating gastric mucosal injury.