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Epigenetic inheritance of heterochromatin requires DNA-sequence-independent propagation mechanisms, coupling to RNAi, or input from DNA sequence, but how DNA contributes to inheritance is not understood. Here, we identify a DNA element (termed "maintainer") that is sufficient for epigenetic inheritance of pre-existing histone H3 lysine 9 methylation (H3K9me) and heterochromatin in Schizosaccharomyces pombe but cannot establish de novo gene silencing in wild-type cells. This maintainer is a composite DNA element with binding sites for the Atf1/Pcr1 and Deb1 transcription factors and the origin recognition complex (ORC), located within a 130-bp region, and can be converted to a silencer in cells with lower rates of H3K9me turnover, suggesting that it participates in recruiting the H3K9 methyltransferase Clr4/Suv39h. These results suggest that, in the absence of RNAi, histone H3K9me is only heritable when it can collaborate with maintainer-associated DNA-binding proteins that help recruit the enzyme responsible for its epigenetic deposition.
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Montagem e Desmontagem da Cromatina , Metilação de DNA , DNA Fúngico/genética , Hereditariedade , Heterocromatina/genética , Sequências Reguladoras de Ácido Nucleico , Schizosaccharomyces/genética , Fatores Ativadores da Transcrição/genética , Fatores Ativadores da Transcrição/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , DNA Fúngico/metabolismo , Epigênese Genética , Regulação Fúngica da Expressão Gênica , Heterocromatina/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Complexo de Reconhecimento de Origem/genética , Complexo de Reconhecimento de Origem/metabolismo , Proteínas/genética , Proteínas/metabolismo , Interferência de RNA , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismoRESUMO
Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) are histone-modifying and -binding complexes that mediate the formation of facultative heterochromatin and are required for silencing of developmental genes and maintenance of cell fate1-3. Multiple pathways of RNA decay work together to establish and maintain heterochromatin in fission yeast, including a recently identified role for a conserved RNA-degradation complex known as the rixosome or RIX1 complex4-6. Whether RNA degradation also has a role in the stability of mammalian heterochromatin remains unknown. Here we show that the rixosome contributes to silencing of many Polycomb targets in human cells. The rixosome associates with human PRC complexes and is enriched at promoters of Polycomb target genes. Depletion of either the rixosome or Polycomb results in accumulation of paused and elongating RNA polymerase at Polycomb target genes. We identify point mutations in the RING1B subunit of PRC1 that disrupt the interaction between PRC1 and the rixosome and result in diminished silencing, suggesting that direct recruitment of the rixosome to chromatin is required for silencing. Finally, we show that the RNA endonuclease and kinase activities of the rixosome and the downstream XRN2 exoribonuclease, which degrades RNAs with 5' monophosphate groups generated by the rixosome, are required for silencing. Our findings suggest that rixosomal degradation of nascent RNA is conserved from fission yeast to human, with a primary role in RNA degradation at facultative heterochromatin in human cells.
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Inativação Gênica , Heterocromatina , Complexo Repressor Polycomb 1 , Estabilidade de RNA , Exorribonucleases/genética , Heterocromatina/genética , Humanos , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 2/genética , Proteínas do Grupo Polycomb/genética , Schizosaccharomyces/genéticaRESUMO
BACKGROUND: Cervical lymph node metastasis (LNM) is an important prognostic factor for patients with non-small cell lung cancer (NSCLC). We aimed to develop and validate machine learning models that use ultrasound radiomic and descriptive semantic features to diagnose cervical LNM in patients with NSCLC. METHODS: This study included NSCLC patients who underwent neck ultrasound examination followed by cervical lymph node (LN) biopsy between January 2019 and January 2022 from three institutes. Radiomic features were extracted from the ultrasound images at the maximum cross-sectional areas of cervical LNs. Logistic regression (LR) and random forest (RF) models were developed. Model performance was assessed by the area under the curve (AUC) and accuracy, validated internally and externally by fivefold cross-validation and hold-out method, respectively. RESULTS: In total, 313 patients with a median age of 64 years were included, and 276 (88.18%) had cervical LNM. Three descriptive semantic features, including long diameter, shape, and corticomedullary boundary, were selected by multivariate analysis. Out of the 474 identified radiomic features, 9 were determined to fit the LR model, while 15 fit the RF model. The average AUCs of the semantic and radiomics models were 0.876 (range: 0.781-0.961) and 0.883 (range: 0.798-0.966), respectively. However, the average AUC was higher for the semantic-radiomics combined LR model (0.901; range: 0.862-0.927). When the RF algorithm was applied, the average AUCs of the radiomics and semantic-radiomics combined models were improved to 0.908 (range: 0.837-0.966) and 0.922 (range: 0.872-0.982), respectively. The models tested by the hold-out method had similar results, with the semantic-radiomics combined RF model achieving the highest AUC value of 0.901 (95% CI, 0.886-0.968). CONCLUSIONS: The ultrasound radiomic models showed potential for accurately diagnosing cervical LNM in patients with NSCLC when integrated with descriptive semantic features. The RF model outperformed the conventional LR model in diagnosing cervical LNM in NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Metástase Linfática , Aprendizado de Máquina , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Pescoço/diagnóstico por imagem , Radiômica , Estudos Retrospectivos , Ultrassonografia/métodosRESUMO
BACKGROUND: The site of lymph node metastasis (LNM) may affect the prognosis of patients with esophageal squamous cell carcinoma (ESCC). To investigate the prognoses of pararespiratory and paradigestive LNM and to propose a novel N (nN) staging system that integrates both the LNM site and count. METHODS: This study was a multicenter, large-sample, retrospective cohort study that included ESCC patients with LNM between January 2014 and December 2019 from three Chinese institutes. Patients were set into training (two institutes) and external validation (one institute) cohorts. The primary outcomes were survival differences in LNM site and the development of novel nodal staging system. The overall survival (OS) of patients with pararespiratory LNM only (Group A), paradigestive LNM only (Group B), and both sites (Group C) was evaluated by Kaplan-Meier. Cox proportional hazards models were used to identify the independent prognostic factors. An nN staging system considering both the LNM site and count was developed and evaluated by the area under the receiver operating characteristic curve (AUC). RESULTS: In total, 1313 patients were included and split into training (n = 1033) and external validation (n = 280) cohorts. There were 342 (26.0%), 568 (43.3%) and 403 (30.7%) patients in groups A, B and C, respectively. The OS of patients with pararespiratory and patients with paradigestive LNM presented significant differences in the training and validation cohorts (P < 0.050). In the training cohort, LNM site was an independent prognostic factor (hazard ratio: 1.58, 95% confidence intervals: 1.41-1.77, P < 0.001). The nN staging definition: nN1 (1-2 positive pararespiratory/paradigestive LNs), nN2 (3-6 pararespiratory LNs or 1 pararespiratory with 1paradigestive LN), nN3 (3-6 LNs with ≥ 1 paradigestive LN), nN4 (≥ 7 LNs). Subsets of patients with different nN stages showed significant differences in OS (P < 0.050). The prognostic model of the nN staging system presented higher performance in the training and validation cohorts at 3-year OS (AUC, 0.725 and 0.751, respectively) and 5-year OS (AUC, 0.740 and 0.793, respectively) than the current N staging systems. CONCLUSIONS: Compared to pararespiratory LNM, the presence of paradigestive LNM is associated with worse OS. The nN staging system revealed superior prognostic ability than current N staging systems.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Povo Asiático , Metástase Linfática , Estudos Retrospectivos , China , Estadiamento de Neoplasias , PrognósticoRESUMO
BACKGROUND: The progress of visceral artery aneurysms (VAAs) after the endovascular repair of artery aneurysms is often accompanies by the potential risks of stent fracture. The clinical reported cases of VAAs stent fractures with stent displacement were extremely rare but severe complication, particularly for the superior mesenteric artery aneurysm (SMAA). METHOD: We here reported a 62-year-old female patient with recurrent symptoms of SMAA 2 years after the successful endovascular repair using coil embolization and two partial overlapping stent-grafts in SMAA. The open surgery was performed instead of secondary endovascular intervention. RESULT AND CONCLUSION: The patient experienced a good recovery. As one of the complications after endovascular repair, stent fracture maybe more dangerous than SMAA itself, the stent fracture after endovascular repair treated by open surgery with satisfactory results is alternative and feasible.
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Fraxinellone, a furanoid, is one of the bioactive and potentially hepatotoxic constituents from Dictamnus dasycarpus Turcz, which is extensively spread throughout Asian countries. This herb was reported to cause liver injury in clinical application. However, the mechanism behind is still not fully understood. This study mainly focused on the hepatotoxicity of fraxinellone and the underlying mechanism. The current study demonstrated that fraxinellone resulted in a significant elevation of serum alanine aminotransferase and aspartate aminotransferase in a dose-dependent manner in mice after oral administration. Pretreatment with ketoconazole for three successive days could significantly alleviate the hepatotoxicity of fraxinellone. Considering that fraxinellone has a structural alert of furan ring, it is believed that the hepatotoxicity caused by fraxinellone required cytochrome P450-mediated bioactivation. Bioactivation studies were subsequently carried out in vitro and in vivo. Fraxinellone was metabolized into cis-enedial intermediate, an electrophile that was prone to react with glutathione or N-acetyl-lysine through 1,2- or 1,4-addition to form stable conjugates. Ketoconazole significantly inhibited the formation of the glutathione conjugates (M1 and M2) in microsomal incubation and similar finding was obtained in vivo. Phenotyping study indicated that CYP3A4 was the principal enzyme responsible for the bioactivation of fraxinellone. This study suggested that CYP3A4-mediated bioactivation plays an indispensable role in fraxinellone-induced hepatotoxicity. The work performed herein enables us to better understand the hepatotoxicity of fraxinellone as well as the mechanism behind.
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Benzofuranos/farmacocinética , Benzofuranos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Ativação Metabólica , Administração Oral , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dictamnus , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND: Spindle microtubule organization, regulated by microtubule-associated proteins, is critical for cell division. Proper organization of kinetochore fiber (K-fiber), connecting spindle poles and kinetochores, is a prerequisite for precise chromosomal alignment and faithful genetic material transmission. However, the mechanisms of K-fiber organization and dynamic maintenance are still not fully understood. RESULTS: We reveal that two previously uncharacterized coiled-coil domain proteins CCDC74A and CCDC74B (CCDC74A/B) are spindle-localized proteins in mammalian cells. They bind directly to microtubules through two separate domains and bundle microtubules both in vivo and in vitro. These functions are required for K-fiber organization, bipolar spindle formation, and chromosomal alignment. Moreover, CCDC74A/B form homodimers in vivo, and their self-association activity is necessary for microtubule bundling and K-fiber formation. CONCLUSIONS: We characterize CCDC74A and CCDC74B as microtubule-associated proteins that localize to spindles and are important K-fiber crosslinkers required for bipolar spindle formation and chromosome alignment.
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Cinetocoros/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Fuso Acromático/metabolismo , Animais , Células COS , Chlorocebus aethiops , Células HEK293 , Células HeLa , Humanos , Proteínas Associadas aos Microtúbulos/genética , MitoseRESUMO
BACKGROUND AND AIMS: Gastric intestinal metaplasia (IM) is common in the gastric epithelium of patients with chronic atrophic gastritis. CDX2 activation in IM is driven by reflux of bile acids and following chronic inflammation. But the mechanism underlying how bile acids activate CDX2 in gastric epithelium has not been fully explored. METHODS: We performed microRNA (miRNA) and messenger RNA (mRNA) profiling using microarray in cells treated with bile acids. Data integration of the miRNA/mRNA profiles with gene ontology (GO) analysis and bioinformatics was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with miRNA mimics and inhibitors was used to evaluate their effects on the expression of candidate targets and functions. Immunohistochemistry and in situhybridisation were used to detect the expression of selected miRNAs and their targets in IM tissue microarrays. RESULTS: We demonstrate a bile acids-triggered pathway involving upregulation of miR-92a-1-5p and suppression of its target FOXD1 in gastric cells. We first found that miR-92a-1-5p was increased in IM tissues and induced by bile acids. Moreover, miR-92a-1-5p was found to activate CDX2 and downstream intestinal markers by targeting FOXD1/FOXJ1 axis and modulating activation of nuclear factor kappa B (NF-κB) pathway. Furthermore, these effects were found to be clinical relevant, as high miR-92a-1-5p levels were correlated with low FOXD1 levels and high CDX2 levels in IM tissues. CONCLUSION: These findings suggest a miR-92a-1-5p/FOXD1/NF-κB/CDX2 regulatory axis plays key roles in the generation of IM phenotype from gastric cells. Suppression of miR-92a-1-5p and restoration of FOXD1 may be a preventive approach for gastric IM in patients with bile regurgitation.
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Fatores de Transcrição Forkhead/genética , Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Gástricas/genética , Ácidos e Sais Biliares/efeitos adversos , Linhagem Celular Tumoral , Fatores de Transcrição Forkhead/metabolismo , Mucosa Gástrica/metabolismo , Humanos , Imuno-Histoquímica , Hibridização In Situ , Metaplasia/genética , Metaplasia/metabolismo , Metaplasia/patologia , MicroRNAs/biossíntese , RNA Neoplásico/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Regulação para CimaRESUMO
Background Gastric cancer (GC) is the second most common cause of cancer-related death worldwide. Novel anticancer drugs against gastric cancer are urgently needed. Methods Compound 10 was designed and synthesized via a molecular hybridization strategy based on the natural product formononetin. It was evaluated for their antiproliferative activity against three gastric cancer cell lines (SGC7901, MKN45 and MGC803). Results Derivative 10 displayed potently antiproliferative activity with an IC50 value of 1.07 µM against SGC7901 cells. Derivative 10 could inhibit the growth and migration against gastric cancer SGC7901 cells through the Wnt/ß-Catenin and AKT/mTOR pathways. From the in vivo expremints, it could effectively inhibited SGC7901 xenograft tumor growth in vivo without significant loss of the body weight. Conclusion Derivative 10 is an novel antitumor agent with potential for further clinical applications to treat gastric cancer. Graphical abstract.
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Antineoplásicos Fitogênicos/uso terapêutico , Cumarínicos/uso terapêutico , Isoflavonas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Cumarínicos/farmacologia , Humanos , Isoflavonas/química , Isoflavonas/farmacologia , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/metabolismo , Carga Tumoral/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
BACKGROUND: TRIP13 is highly expressed in several cancers and is closely connected with cancer progression. However, its roles on the growth and metastasis of hepatocellular carcinoma (HCC), and the underlying mechanism are still unclear. METHODS: Combining bioinformatics with previous studies, the correlation between TRIP13 and HCC was predicted. TRIP13 expressions from 52 HCC patients and several cell lines were determined. The effects of silencing TRIP13 on cell viability, apoptosis, migration and invasion were respectively detected using CCK-8, flow cytometry and Transwell. qRT-PCR and western blot were performed to reveal associated mechanism. A HCC model was established in BALB/c-nu mice by transplanting HepG2 cells. TRIP13 protein expression and apoptosis in mice tissues were accordingly detected by Immunohistochemistry and TUNEL. RESULTS: High expression of TRIP13 in HCC affected the survival rate and it was enriched in RNA degradation and fatty acid metabolism according to bioinformatics and prediction from previous literature. Increased expression of TRIP13 in HCC patient tissues was associated with the progression of HCC. Silencing TRIP13 inhibited cell viability, migration and invasion, and induced cell apoptosis. TRIP13 knockdown also suppressed the formation of tumor in vivo. Meanwhile, silencing TRIP13 decreased the expressions of Ki67 and MMP-2 and increased the expressions of TIMP-2, active-caspase-3 and TGF-ß1/smad3 signaling- related genes. CONCLUSIONS: Silencing TRIP13 acts as a tumor suppresser of HCC to repress cell growth and metastasis in vitro and in vivo, and such a phenomenon possibly involved activation of TGF-ß1/smad3 signaling.
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Cytokinesis is the final stage of cell division in which the cytoplasm of a cell is divided into two daughter cells after the segregation of genetic material, and the central spindle and midbody are considered to be the essential structures required for the initiation and completion of cytokinesis. Here, we determined that the centrosome protein Cep57, which is localized to the central spindle and midbody, acts as a spindle organizer and is required for cytokinesis. Depletion of Cep57 disrupted microtubule assembly of the central spindle and further led to abnormal midbody localization of MKLP1, Plk1, and Aurora B, which resulted in cytokinesis failure and the formation of binuclear cells. Furthermore, we found that Cep57 directly recruited Tektin 1 to the midbody matrix to regulate microtubule organization. Thus, our data reveal that Cep57 is essential for cytokinesis via regulation of central spindle assembly and formation of the midbody.
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Proteínas de Transporte/fisiologia , Citocinese/fisiologia , Regulação da Expressão Gênica , Proteínas Associadas aos Microtúbulos/fisiologia , Microtúbulos/metabolismo , Proteínas Nucleares/fisiologia , Fuso Acromático/metabolismo , Animais , Proteínas de Ciclo Celular , Centrossomo/metabolismo , Células HEK293 , Células HeLa , Humanos , Camundongos , Proteínas dos Microtúbulos/metabolismo , Mitose , Plasmídeos/metabolismo , Ligação ProteicaAssuntos
Adenocarcinoma de Pulmão/diagnóstico , Brônquios/diagnóstico por imagem , Cisto Broncogênico/diagnóstico , Neoplasias Pulmonares/diagnóstico , Adenocarcinoma de Pulmão/cirurgia , Biópsia , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pneumonectomia , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
The current use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has dramatically changed the clinical strategy for metastatic non-small cell lung cancer (mNSCLC). As a result of great achievements in clinical trials, 6 programmed death-1 inhibitors (sintilimab, camrelizumab, tislelizumab, pembrolizumab, cemiplimab, and nivolumab), 2 programmed death-ligand 1 inhibitors (sugemalimab and atezolizumab), and 1 cytotoxic T lymphocyte-associated antigen-4 inhibitor (ipilimumab) have been approved as first-line treatment for mNSCLC by the US Food and Drug Administration. Recently, research on ICIs has shifted from a large number of second-line to first-line settings in clinical trials. Results from first-line trials have shown that almost all driver-negative mNSCLC are treated with ICIs and significantly prolong patient survival; however, the low response rate and adverse reactions to immunotherapy remain to be addressed. Here, we summarize the use of ICIs, including monotherapy and combination therapy, in the first-line treatment of mNSCLC in recent years and discuss the low response rate and adverse reactions of ICIs as well as the challenges and expectations for the first-line treatment of mNSCLC in the future.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Ipilimumab/uso terapêutico , Imunoterapia/métodosRESUMO
The spindle assembly checkpoint (SAC) ensures chromosome segregation fidelity by manipulating unattached kinetochore-dependent assembly of the mitotic checkpoint complex (MCC). The MCC binds to and inhibits the anaphase promoting complex/cyclosome (APC/C) to postpone mitotic exit. However, the mechanism by which unattached kinetochores mediate MCC formation is not yet fully understood. Here, it is shown that CCDC68 is an outer kinetochore protein that preferentially localizes to unattached kinetochores. Furthermore, CCDC68 interacts with the SAC factor CDC20 to inhibit its autoubiquitination and MCC disassembly. Therefore, CCDC68 restrains APC/C activation to ensure a robust SAC and allow sufficient time for chromosome alignment, thus ensuring chromosomal stability. Hence, the study reveals that CCDC68 is required for CDC20-dependent MCC stabilization to maintain mitotic checkpoint activation.
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Polycomb repressive complexes 1 and 2 (PRC1 and 2) are required for heritable repression of developmental genes. The cis- and trans-acting factors that contribute to epigenetic inheritance of mammalian Polycomb repression are not fully understood. Here, we show that, in human cells, ectopically induced Polycomb silencing at initially active developmental genes, but not near ubiquitously expressed housekeeping genes, is inherited for many cell divisions. Unexpectedly, silencing is heritable in cells with mutations in the H3K27me3 binding pocket of the Embryonic Ectoderm Development (EED) subunit of PRC2, which are known to disrupt H3K27me3 recognition and lead to loss of H3K27me3. This mode of inheritance is less stable and requires intact PRC2 and recognition of H2AK119ub1 by PRC1. Our findings suggest that maintenance of Polycomb silencing is sensitive to local genomic context and can be mediated by PRC1-dependent H2AK119ub1 and PRC2 independently of H3K27me3 recognition.
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Inativação Gênica , Histonas , Proteínas do Grupo Polycomb , Ubiquitinação , Humanos , Histonas/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Proteínas do Grupo Polycomb/genética , Complexo Repressor Polycomb 2/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 1/genética , Genoma Humano , Epigênese Genética , MutaçãoRESUMO
BACKGROUND: Lymph node metastasis is significantly associated with a worse prognosis in patients with localized early-stage esophageal squamous cell carcinoma. This study aimed to explore the prognostic factors and develop a nomogram for predicting survival in patients with pathologic T1-2N+ esophageal squamous cell carcinoma. METHODS: Between 2014 and 2022, patients with pT1-2N+ esophageal squamous cell carcinoma who underwent esophagectomy with lymphadenectomy at 2 institutes were reviewed and assigned to training and external validation cohorts. Independent prognostic factors were identified via univariate and multivariate Cox regression analyses. The nomogram model was developed and evaluated by the area under the receiver operating characteristic curve and calibration curve. RESULTS: In total, 268 patients with a median age of 65 years (range, 40-82) were included and assigned to training (n = 190) and external validation (n = 78) cohorts. The Cox proportional hazards model demonstrated that body mass index (P = .031), surgical approach (P < .001), T stage (P = .015), and Clavien-Dindo classification (P < .001) were independent prognostic factors in the training cohort. The nomogram showed good discrimination, with an area under the receiver operating characteristic curve for 1-year, 3-year, and 5-year of 0.810, 0.789, and 0.809 in the training cohort and 0.782, 0.679, and 0.698 in the validation cohort. The calibration curve showed that the predicted survival probability was in good agreement with the actual survival probability. CONCLUSION: Lower body mass index, left surgical approach, T2 stage, and Clavien-Dindo classification grade III to V were related to worse prognosis in patients with pT1-T2N+ esophageal squamous cell carcinoma. The developed nomogram may predict individual survival accurately.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Esofagectomia , Estadiamento de Neoplasias , Nomogramas , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Estudos Retrospectivos , Idoso , Carcinoma de Células Escamosas do Esôfago/cirurgia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Prognóstico , Adulto , Idoso de 80 Anos ou mais , Metástase Linfática , Excisão de Linfonodo , Curva ROC , Modelos de Riscos ProporcionaisRESUMO
OBJECTIVE: The primary purpose of the study was to explore the clinical efficacy of the novel snare assisted endoscopic resection of extraluminal growing gastric gastrointestinal stromal tumors (gastric GISTs) using external traction, and the secondary purpose was to compare the novel snare assisted endoscopic resection of extraluminal GISTs with the standard laparoscopic procedure. METHODS: We retrospectively analyzed the patients who underwent novel external traction assisted endoscopic resection or laparoscopic resection for their extraluminal gastric GIST ≤5 cm in diameter. RESULTS: A total of 111 patients (27 in the endoscopic group and 84 in the laparoscopic group) were included in this study. There was no significant difference in tumor diameter and complication rate between the two groups. The overall procedure time was slightly higher in the endoscopic group compared to the laparoscopic group (P = 0.034). However, postoperative hospitalization time (P < 0.001) and postoperative fasting time (P = 0.005) were shorter in the endoscopic group compared to the laparoscopic group. CONCLUSION: Snare external traction-assisted endoscopic resection of extraluminal growing gastric GISTs is safe and effective, and it provides a new adjunctive method for endoscopic resection of GIST.
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Diffuse large B-cell lymphoma is the most common subtype of lymphoma, representing â¼25 % of non-Hodgkin lymphoid malignancies. EZH2 is highly expressed in Diffuse large B-cell lymphoma and â¼22 % of patients contain EZH2 mutations. EZH2 have been studied as a potential therapeutic target for a decade, but efficient inhibition of EZH2 did not robustly kill lymphoma cells. Here, we found that EZH2 mediates repression of oncogenic genes STAT3 and USP7 in Diffuse large B-cell lymphoma cells. Inhibition of EZH2 leads to upregulation of STAT3 and USP7 at both RNA and protein levels. Along with USP7 upregulation, MDM2 is upregulated and its ubiquitylation substrate, Tumor suppressor P53, is downregulated. Upregulation of STAT3 and downregulation of p53 can strength cell proliferation and prevent cells from apoptosis, which suggests resistance mechanisms by which cells survive EZH2 inhibition-induced cell death. Short-course co-inhibition of USP7 and EZH2 showed increased apoptosis and cell proliferation prevention with the concentration as low as 0.08 µM. In STAT3 and USP7 depleted cells, EZH2 inhibition shows superior efficacy of apoptosis, and in EZH2 depleted cells, USP7 inhibition also shows superior efficacy of apoptosis. Thus, our findings suggest a new precision therapy by combinational inhibition of EZH2 with STAT3 or USP7 for Diffuse large B-cell lymphoma.
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The rixosome and PRC1 silencing complexes are associated with deSUMOylating and deubiquitinating enzymes, SENP3 and USP7, respectively. How deSUMOylation and deubiquitylation contribute to rixosome- and Polycomb-mediated silencing is not fully understood. Here, we show that the enzymatic activities of SENP3 and USP7 are required for silencing of Polycomb target genes. SENP3 deSUMOylates several rixosome subunits, and this activity is required for association of the rixosome with PRC1. USP7 associates with canonical PRC1 (cPRC1) and deubiquitinates the chromodomain subunits CBX2 and CBX4, and inhibition of USP activity results in disassembly of cPRC1. Finally, both SENP3 and USP7 are required for Polycomb- and rixosome-dependent silencing at an ectopic reporter locus. These findings demonstrate that SUMOylation and ubiquitination regulate the assembly and activities of the rixosome and Polycomb complexes and raise the possibility that these modifications provide regulatory mechanisms that may be utilized during development or in response to environmental challenges.