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AIM: To compare the performance and reading time of different readers using automatic artificial intelligence (AI)-powered computer-aided detection (CAD) to detect lung nodules in different reading modes. MATERIALS AND METHODS: One hundred and fifty multidetector computed tomography (CT) datasets containing 340 nodules ≤10 mm in diameter were collected retrospectively. A CAD with vessel-suppressed function was used to interpret the images. Three junior and three senior readers were assigned to read (1) CT images without CAD, (2) second-read using CAD in which CAD was applied only after initial unassisted assessment, and (3) a concurrent read with CAD in which CAD was applied at the start of assessment. Diagnostic performances and reading times were compared using analysis of variance. RESULTS: For all readers, the mean sensitivity improved from 64% (95% confidence interval [CI]: 62%, 66%) for the without-CAD mode to 82% (95% CI: 80%, 84%) for the second-reading mode and to 80% (95% CI: 79%, 82%) for the concurrent-reading mode (p<0.001). There was no significant difference between the two modes in terms of the mean sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) for both junior and senior readers and all readers (p>0.05). The reading time of all readers was significantly shorter for the concurrent-reading mode (124 ± 25 seconds) compared to without CAD (156 ± 34 seconds; p<0.001) and the second-reading mode (197 ± 46 seconds; p<0.001). CONCLUSION: In CAD for lung nodules at CT, the second-reading mode and concurrent-reading mode may improve detection performance for all readers in both screening and clinical routine practice. Concurrent use of CAD is more efficient for both junior and senior readers.
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Inteligência Artificial , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada Multidetectores/métodos , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Feminino , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , TempoRESUMO
AIMS: Bipolar disorder is associated with premature mortality, but evidence is mostly derived from Western countries. There has been no research evaluating shortened lifespan in bipolar disorder using life-years lost (LYLs), which is a recently developed mortality metric taking into account illness onset for life expectancy estimation. The current study aimed to examine the extent of premature mortality in bipolar disorder patients relative to the general population in Hong Kong (HK) in terms of standardised mortality ratio (SMR) and excess LYLs, and changes of mortality rate over time. METHODS: This population-based cohort study investigated excess mortality in 12 556 bipolar disorder patients between 2008 and 2018, by estimating all-cause and cause-specific SMRs, and LYLs. Trends in annual SMRs over the 11-year study period were assessed. Study data were retrieved from a territory-wide medical-record database of HK public healthcare services. RESULTS: Patients had higher all-cause [SMR: 2.60 (95% CI: 2.45-2.76)], natural-cause [SMR: 1.90 (95% CI: 1.76-2.05)] and unnatural-cause [SMR: 8.63 (95% CI: 7.34-10.03)] mortality rates than the general population. Respiratory diseases, cardiovascular diseases and cancers accounted for the majority of deaths. Men and women with bipolar disorder had 6.78 (95% CI: 6.00-7.84) years and 7.35 (95% CI: 6.75-8.06) years of excess LYLs, respectively. The overall mortality gap remained similar over time, albeit slightly improved in men with bipolar disorder. CONCLUSIONS: Bipolar disorder is associated with increased premature mortality and substantially reduced lifespan in a predominantly Chinese population, with excess deaths mainly attributed to natural causes. Persistent mortality gap underscores an urgent need for targeted interventions to improve physical health of patients with bipolar disorder.
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Transtorno Bipolar , Transtorno Bipolar/epidemiologia , Causas de Morte , Estudos de Coortes , Feminino , Hong Kong/epidemiologia , Humanos , Expectativa de Vida , MasculinoRESUMO
OBJECTIVES: The co-occurrence of different classes of population-level stressors, such as social unrest and public health crises, is common in contemporary societies. Yet, few studies explored their combined mental health impact. The aim of this study was to examine the impact of repeated exposure to social unrest-related traumatic events (TEs), coronavirus disease 2019 (COVID-19) pandemic-related events (PEs), and stressful life events (SLEs) on post-traumatic stress disorder (PTSD) and depressive symptoms, and the potential mediating role of event-based rumination (rumination of TEs-related anger, injustice, guilt, and insecurity) between TEs and PTSD symptoms. METHODS: Community members in Hong Kong who had utilized a screening tool for PTSD and depressive symptoms were invited to complete a survey on exposure to stressful events and event-based rumination. RESULTS: A total of 10,110 individuals completed the survey. Hierarchical regression analysis showed that rumination, TEs, and SLEs were among the significant predictors for PTSD symptoms (all P < 0.001), accounting for 32% of the variance. For depression, rumination, SLEs, and PEs were among the significant predictors (all P < 0.001), explaining 24.9% of the variance. Two-way analysis of variance of different recent and prior TEs showed significant dose-effect relationships. The effect of recent TEs on PTSD symptoms was potentiated by prior TEs (P = 0.005). COVID-19 PEs and prior TEs additively contributed to PTSD symptoms, with no significant interaction (P = 0.94). Meanwhile, recent TEs were also potentiated by SLEs (P = 0.002). The effects of TEs on PTSD symptoms were mediated by rumination (ß = 0.38, standard error = 0.01, 95% confidence interval: 0.36 to 0.41), with 40.4% of the total effect explained. All 4 rumination subtypes were significant mediators. CONCLUSIONS: Prior and ongoing TEs, PEs, and SLEs cumulatively exacerbated PTSD and depressive symptoms. The role of event-based rumination and their interventions should be prioritized for future research.
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COVID-19 , Depressão , Ruminação Cognitiva/classificação , Transtornos de Estresse Pós-Traumáticos , Estresse Psicológico , Adulto , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/psicologia , Controle de Doenças Transmissíveis/métodos , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/etiologia , Feminino , Hong Kong/epidemiologia , Humanos , Acontecimentos que Mudam a Vida , Masculino , Programas de Rastreamento/métodos , Saúde Mental , Técnicas Psicológicas , Saúde Pública , Medição de Risco , SARS-CoV-2 , Fatores Sociológicos , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Estresse Psicológico/epidemiologia , Estresse Psicológico/etiologia , Inquéritos e QuestionáriosRESUMO
Objective: To obtain biomarkers of allergic rhinitis (AR) by performing bioinformatics analysis on gene chips related to allergic rhinitis in the Gene Expression Database (GEO). Methods: From June 2018 to December 2019, we downloaded data (GSE46171) involving 3 control individuals and 6 AR patients from the publicallyavailable Gene Expression Omnibus database (GEO,http://www.ncbi.nlm.nih.gov/geo), and differentially expressed genes (DEGs) were screened between AR and normal tissues by using the GEO2R online tool comprehensively. Then, we used the bioinformatics methods, including Gene Ontology (GO) analysis and Kyoto Encyclopedia of Gene, Genome (KEGG) pathway analysis and protein-protein interaction (PPI) network construction to identify key genes in AR. In the same period, the inferior turbinate mucosa tissues of 15 AR patients and 15 healthy controls were collected during operationinthe Department of Otolaryngology Head and Neck Surgery of the People 's Hospital of Wuhan Universityto further verify important genes and pathways and perform real-time quantitative PCR.SPSS9.0 statistical software was used for statistical analysis. Results: Two hundred and seventeen DEGs genes were selected, of which 112 were down-regulated genes and 105 were up-regulated genes. Among them, the five up-regulated genes with the most significant differences were KLK7, TMPRSS11A, SPRR2C, TPSAB1, and TXLNGY; the five down-regulated genes with the most significant differences were: XIST, CTAG1A, PRB1, CXCL11 and PRB2. By constructing a PPI network among 217 DEGs, the 15 hub genes obtained were IFIH1, CCR2, CD80, TLR7, EIF1AY, DDX3Y, RSAD2, RPS4Y2, RPS4Y1, XAF1, KDM5D, ZFY, NLGN4Y, IFIT5 and DDX60L, these Genes were at a hub in a gene network. We collected inferior turbinate mucosa tissue during surgery,and these 15 genes were verified, and the expressions of IFIH1, CCR2, CD80, TLR7, RSAD2, XAF1, IFIT5 and DDX60L were reduced, wherea the expressions of EIF1AY, DDX3Y, RPS4Y2, RPS4Y1, KDM5D, ZFY and NLGN4Y were increased, differences were statistically significant (all P<0.05). Conclusions: The study finds 217 genes closely related to allergic rhinitis and obtains 15 hub genes through the PPI network. These genes may be involved in the pathogenesis of allergic rhinitis and are expected to become new biomarkers for allergic rhinitis.
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Biologia Computacional , Rinite Alérgica , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Biomarcadores/análise , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Histona Desmetilases , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Antígenos de Histocompatibilidade Menor , Rinite Alérgica/genética , TriptasesRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Inhibitors against poly (ADP-ribose) polymerase (PARP) are promising targeted agents currently used to treat BRCA-mutant ovarian cancer and are in clinical trials for other cancer types, including BRCA-mutant breast cancer. To enhance the clinical response to PARP inhibitors (PARPis), understanding the mechanisms underlying PARPi sensitivity is urgently needed. Here, we show enhancer of zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation and associates with oncogenic function, contributes to PARPi sensitivity in breast cancer cells. Mechanistically, upon oxidative stress or alkylating DNA damage, PARP1 interacts with and attaches poly-ADP-ribose (PAR) chains to EZH2. PARylation of EZH2 by PARP1 then induces PRC2 complex dissociation and EZH2 downregulation, which in turn reduces EZH2-mediated H3 trimethylation. In contrast, inhibition of PARP by PARPi attenuates alkylating DNA damage-induced EZH2 downregulation, thereby promoting EZH2-mediated gene silencing and cancer stem cell property compared with PARPi-untreated cells. Moreover, the addition of an EZH2 inhibitor sensitizes the BRCA-mutant breast cells to PARPi. Thus, these results may provide a rationale for combining PARP and EZH2 inhibition as a therapeutic strategy for BRCA-mutated breast and ovarian cancers.
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Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , ADP-Ribosilação/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Dano ao DNA , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Inativação Gênica , Humanos , Camundongos , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Steroidogenesis-mediated production of neurosteroids is important for brain homeostasis. Cytochrome P450 17A1 (CYP17A1), which converts pregnenolone to dehydroepiandrosterone (DHEA) in endocrine organs and the brain, is required for prostate cancer progression and acquired chemotherapeutic resistance. However, whether CYP17A1-mediated DHEA synthesis is involved in brain tumor malignancy, especially in glioma, the most prevalent brain tumor, is unknown. To investigate the role of CYP17A1 in glioma, we determined that CYP17A1 expression is significantly increased in gliomas, which secrete more DHEA than normal astrocytes. We found that as gliomas became more malignant, both CYP17A1 and DHEA were significantly upregulated in temozolomide (TMZ)-resistant cells and highly invasive cells. In particular, the increase of CYP17A1 was caused by Sp1-mediated DNA demethylation, whereby Sp1 competed with DNMT3a for binding to the CYP17A1 promoter in TMZ-resistant glioma cells. CYP17A1 was required for the development of glioma cell invasiveness and resistance to TMZ-induced cytotoxicity. In addition, DHEA markedly attenuated TMZ-induced DNA damage and apoptosis. Together, our results suggest that components of the Sp1-CYP17A1-DHEA axis, which promotes the development of TMZ resistance, may serve as potential biomarkers and therapeutic targets in recurrent glioma.
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Heat shock protein 90 (HSP90), which is expressed in cancer cells, profoundly affects progression, invasion, and metastasis. However, to our knowledge, in East Asia, the correlation between the expression of HSP90 and clinicopathological variables has seldom been discussed. We therefore investigated this and its prognostic value in 36 patients newly diagnosed with oral squamous cell carcinoma (SCC) in northern Taiwan. Samples of tumour and normal samples from the patients were compared immunohistochemically. HSP90 was expressed mainly in the samples of tumour, and was significantly higher in these than in the normal epithelium (p<0.001). Metastases to the lymph nodes in the 36 patients also correlated with expression of HSP90. Correlation between expression of HSP90 and the size of the tumour or pathological staging was not significant, but strong expression correlated with poor survival. In general, expression was low among our samples (30/36). It was significantly higher in the tumour samples than in normal samples, and correlated with metastases to lymph nodes in the neck.
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Carcinoma de Células Escamosas/metabolismo , Proteínas de Choque Térmico HSP90/biossíntese , Neoplasias Bucais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/mortalidade , Taxa de Sobrevida , TaiwanRESUMO
The Yes-associated protein (YAP) is an effector that transduces the output of the Hippo pathway to transcriptional modulation. Considering the role of YAP in cancers, this protein has emerged as a key node in malignancy development. In this study, we determined that Aurora A kinase acts as a positive regulator for YAP-mediated transcriptional machinery. Specifically, YAP associates with Aurora A predominantly in the nucleus. Activation of Aurora A can impinge on YAP activity through direct phosphorylation. Moreover, aberrant expression of YAP and Aurora A signaling is highly correlated with triple-negative breast cancer (TNBC). We herein provide evidence to establish the functional relevance of this newly discovered regulatory axis in TNBC.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aurora Quinase A/metabolismo , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Fosfoproteínas/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Apoptose , Humanos , Técnicas Imunoenzimáticas , Camundongos , Células NIH 3T3 , Fosforilação , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAPRESUMO
In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. Silencing USP24 increases the cancer formation by inhibiting cellular apoptosis and increasing cellular proliferation. Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. Knockdown of USP24 decreases Bax and p300 levels, and reduces Ku70 acetylation, thereby preventing cancer cell apoptosis. In addition, knockdown of USP24 increases cell cycle progression by enhancing the G1-S transition and metaphase-anaphase transition. The molecular mechanism involves a decrease in the USP24 level, which reduces the expression of E2F4 and its partner TFDP1, and thus increases the G1/S transition. In conclusion, the USP24 level was decreased during the early stage of cancer and the mitotic stage of the cell cycle to regulate its substrates p300, Bax, E2F4 and securin, resulting in decreased cell apoptosis and increased cell cycle progression and, thus, cancer formation.
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Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Fator de Crescimento Epidérmico/farmacologia , Ubiquitina Tiolesterase/genética , Células A549 , Animais , Ciclo Celular/genética , Linhagem Celular Tumoral , Proteína p300 Associada a E1A/genética , Fator de Transcrição E2F4/genética , Fator de Crescimento Epidérmico/fisiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Camundongos , Camundongos Transgênicos , Securina/genética , Proteína X Associada a bcl-2/genéticaRESUMO
Heat-shock protein 5 (HSPA5) is a marker for poor prognosis in breast cancer patients and has an important role in cancer progression, including promoting drug resistance and metastasis. In this study, we identify that the specific lysine residue 447 (K447) of HSPA5 could be modified with polyubiquitin for subsequent degradation through the ubiquitin proteasomal system, leading to the suppression of cell migration and invasion of breast cancer. We further found that GP78, an E3 ubiquitin ligase, interacted with the C-terminal region of HSPA5 and mediated HSPA5 ubiquitination and degradation. Knock down of GP78 significantly increased the expression of HSPA5 and enhanced migration/invasive ability of breast cancer cells. Knock down of histone deacetylase-6 (HDAC6) increased the acetylation of HSPA5 at lysine residues 353 (K353) and reduced GP78-mediated ubiquitination of HSPA5 at K447 and then increased cell migration/invasion. In addition, we demonstrate that E3 ubiquitin ligase GP78 preferentially binds to deacetylated HSPA5. Notably, the expression levels of GP78 inversely correlated with HSPA5 levels in breast cancer patients. Patients with low GP78 expression significantly correlated with invasiveness of breast cancer, advanced tumor stages and poor clinical outcome. Taken together, our results provide new mechanistic insights into the understanding that deacetylation of HSPA5 by HDAC6 facilitates GP78-mediated HSPA5 ubiquitination and suggest that post-translational regulation of HSPA5 protein is critical for HSPA5-mediated metastatic properties of breast cancer.
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Neoplasias da Mama/metabolismo , Proteínas de Choque Térmico/metabolismo , Histona Desacetilases/metabolismo , Acetilação , Sequência de Aminoácidos , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Chaperona BiP do Retículo Endoplasmático , Feminino , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/genética , Desacetilase 6 de Histona , Histona Desacetilases/genética , Humanos , Camundongos SCID , Dados de Sequência Molecular , Invasividade Neoplásica , Metástase Neoplásica , Complexo de Endopeptidases do Proteassoma/metabolismo , Homologia de Sequência de Aminoácidos , UbiquitinaçãoRESUMO
Ubiquitin is a critical modifier regulating the degradation and function of its target proteins during posttranslational modification. Here we found that ubiquitin-specific peptidase 24 (USP24) is highly expressed in cell lines with enhanced malignancy and in late-stage lung cancer clinical samples. Studying single-nucleotide polymorphisms (SNPs) of USP24 using genomic DNA of lung cancer patients revealed an increase in SNP 7656C/T. When using RNA specimens instead of the genomic DNA of lung cancer patients, we found significant increases in the ratios of variants 930C/T and 7656T/C, suggesting that variants at these two sites are not only caused by the SNP of DNA but also by the RNA editing. USP24-930T and USP24-7656C increase USP24 expression levels by increasing RNA stability. Knocking down USP24 increased Suv39h1 level through a decrease in mouse double-minute 2 homolog levels, thus enhancing lysine-9 methylation of histone H3, and resulting in the prevention of lung cancer malignancy. In conclusion, as USP24 variant analysis revealed a higher ratio of variants in blood specimens of lung cancer patients than that in normal individuals, USP24-930T and USP24-7656C might be useful as diagnostic markers for cancer detection.
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Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Ubiquitina Tiolesterase/genética , Células A549 , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/metabolismo , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Interferência de RNA , Estabilidade de RNA/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sobrevida , Transplante Heterólogo , Ubiquitina Tiolesterase/metabolismoRESUMO
BACKGROUND: Malignancy is known to be associated with an increased mortality rate in patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, risk factors contributing to the poor prognosis of patients with SJS/TEN with malignancies remain undefined. OBJECTIVES: To explore the potential involvement of malignancy and its related factors contributing to the poor outcome of SJS/TEN, in a retrospective study. METHODS: In total 517 patients with SJS/TEN were enrolled. Forty-seven who sustained various types of malignancies were analysed for numerous malignancy-related factors, including cancer types, clinical stages and chemotherapies given or not before the onset of SJS/TEN. RESULTS: We found that the mortality rate of patients with SJS/TEN with malignancies was higher than that of patients without malignancies (32%, 15/47 vs. 8·5%, 40/470, respectively) (P < 0·001). The use of phenytoin was significantly higher in the malignancy group. The presence of hepatocellular carcinoma (80%, four of five; P < 0·001; odds ratio 43) and colorectal cancer (67%, two of three; P = 0·022; odds ratio 21·5) significantly increased the death rate of patients with SJS/TEN, whereas lung cancer and urothelial carcinoma did not. Patients who had received ongoing or recent chemotherapy showed higher mortality than those without chemotherapy (P = 0·022; odds ratio 4·95). Furthermore, among the 47 patients with SJS/TEN with malignancies, lower serum albumin, haemoglobin and platelet count were detected in the deceased patients than in the surviving patients before the onset of SJS/TEN. CONCLUSIONS: Our results suggest that several factors related to malignancies, such as specific cancer types, chemotherapy and malnutrition, may contribute to poor prognosis in patients with malignancies developing SJS/TEN.
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Neoplasias/mortalidade , Síndrome de Stevens-Johnson/mortalidade , Antibacterianos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticonvulsivantes/efeitos adversos , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Sepse/mortalidade , Síndrome de Stevens-Johnson/complicações , Taiwan/epidemiologiaRESUMO
Tumor metastasis is the major cause of death among cancer patients, with >90% of cancer-related death attributable to the spreading of metastatic cells to secondary organs. Store-operated Ca(2+) entry (SOCE) is the predominant Ca(2+) entry mechanism in most cancer cells, and stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum (ER) Ca(2+) sensor for store-operated channels. Here we reported that the STIM1 was overexpressed in colorectal cancer (CRC) patients. STIM1 overexpression in CRC was significantly associated with tumor size, depth of invasion, lymph node metastasis status and serum levels of carcinoembryonic antigen. Furthermore, ectopic expression of STIM1 promoted CRC cell motility, while depletion of STIM1 with short hairpin RNA inhibited CRC cell migration. Our data further suggested that STIM1 promoted CRC cell migration through increasing the expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). Importantly, ectopically expressed COX-2 or exogenous PGE2 were able to rescue migration defect in STIM1 knockdown CRC cells, and inhibition of COX-2 with ibuprofen and indomethacin abrogated STIM1-mediated CRC cell motility. In short, our data provided clinicopathological significance for STIM1 and SOCE in CRC progression, and implicated a role for COX-2 in STIM1-mediated CRC metastasis. Our studies also suggested a new approach to inhibit STIM1-mediated metastasis with COX-2 inhibitors.
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Movimento Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ciclo-Oxigenase 2/genética , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Células CACO-2 , Antígeno Carcinoembrionário/sangue , Linhagem Celular Tumoral , Neoplasias Colorretais/sangue , Dinoprostona/genética , Progressão da Doença , Feminino , Células HCT116 , Células HT29 , Humanos , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/genética , Molécula 1 de Interação EstromalRESUMO
Nucleolin (NCL) participates in DNA transcription, ribosomal biogenesis and the regulation of RNA stability. However, the contribution of NCL to tumor development is still not clear. Herein, we found that NCL expression correlated with poor prognosis in lung cancer patients. Overexpressed NCL was predominantly cleaved to C-terminal truncated NCL (TNCL). In lung cancer formation, activation of the epidermal growth factor receptor pathway induced NCL expression, and also the expression of matrix metalloproteinase (MMP) 7, which then cleaved NCL at Asp255 to generate TNCL of 55 kDa. TNCL increased the expression of several oncogenes, including MMP9, anaplastic lymphoma kinase (ALK), HIF1a and CBLB, and decreased the expression of tumor suppressors including BRD4, PCM1, TFG and KLF6 by modulating mRNA stability through binding to the 3'-untranslated regions of their transcripts, thus ultimately enhancing metastasis activity. In conclusion, this study identified a novel role of the cleavage form of NCL generated by MMP7 in stabilizing MMP9 mRNA. We also provide a new insight that MMP7 not only cleaves the extracellular matrix to promote tumor invasion but also cleaves NCL, which augment oncogenesis. Blocking NCL cleavage may provide a useful new strategy for lung cancer therapy.
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Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Fosfoproteínas/metabolismo , Proteólise , Proteínas de Ligação a RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso , Quinase do Linfoma Anaplásico , Animais , Autoantígenos/genética , Autoantígenos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator 6 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Nus , Metástase Neoplásica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Proteínas de Ligação a RNA/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , NucleolinaAssuntos
Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Ovarianas/diagnóstico , Teratoma/diagnóstico , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Achados Incidentais , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
BACKGROUND: The role of surgery in the management of large hepatocellular carcinomas (HCCs) is controversial. Advanced age and comorbidities are taken into account when major surgery is considered. PURPOSE: To compare the outcomes of liver resection (LR) and transarterial chemoembolization (TACE) for resectable HCC in patients aged 70 years or older. PATIENTS AND MATERIALS: This study included 70 patients aged 70 years or older treated for large HCCs (≥5 cm) between January 2007 and December 2012: 37 underwent LR and 33 underwent TACE. The outcomes of these patients were retrospectively analyzed. Univariate and multivariate Cox proportional hazard models were established. Kaplan-Meier survival curves were generated, and survival data were compared using the log-rank test. RESULTS: Hospital stay was significantly longer in the LR group than in the TACE group (10 days vs 8.5 days; P = 0.003). Treatment-related complications were more frequent in the TACE group, but this difference was not statistically significant. LR was associated with a better disease-free survival rate, median survival rate and cumulative overall survival rate. CONCLUSION: Our results showed that LR could be a safe and effective treatment option for HCC tumors ≥5 cm in patiets aged 70 years or older.
Assuntos
Fatores Etários , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Contraindicações , Intervalo Livre de Doença , Feminino , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Tempo de Internação , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: Mullerian adenosarcoma usually originates in the endometrium and grows as a polypoid mass in post-menopausal women presenting as abnormal vaginal bleeding. This report reviewed Miillerian adenosarcoma cases to clarify the clinical and pathologic characteristics. MATERIALS AND METHODS: Fifteen cases ofMiillerian adenosarcoma in two medical centers covering a 15-year period were reviewed. Their clinical characteristics, pathologic findings, treatment, and outcomes were compared. RESULTS: Of the 15 cases, three originated from the endometrium, six arose from uterine adenomyosis, three from the adnexa, and three from the cervix. There was only one post-menopausal case. One case was of breast cancer with tamoxifen (TMX) therapy. There were four Miillerian adenosarcoma with sarcomatous overgrowth (MASO) cases, three of which died within one year after surgery. Only the focal MASO case survived. CONCLUSION: The rare variant of MASO is very aggressive and associated with poor prognosis.
Assuntos
Adenossarcoma/terapia , Neoplasias Uterinas/terapia , Adenossarcoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Uterinas/patologiaRESUMO
Squamous cell carcinoma (SCC) cells refractory to initial chemotherapy frequently develop disease relapse and distant metastasis. We show here that tumor suppressor WW domain-containing oxidoreductase (WWOX) (also named FOR or WOX1) regulates the susceptibility of SCC to methotrexate (MTX) in vitro and cure of SCC in MTX therapy. MTX increased WWOX expression, accompanied by caspase activation and apoptosis, in MTX-sensitive SCC cell lines and tumor biopsies. Suppression by a dominant-negative or small interfering RNA targeting WWOX blocked MTX-mediated cell death in sensitive SCC-15 cells that highly expressed WWOX. In stark contrast, SCC-9 cells expressed minimum amount of WWOX protein and resisted MTX-induced apoptosis. Transiently overexpressed WWOX sensitized SCC-9 cells to apoptosis by MTX. MTX significantly downregulated autophagy-related Beclin-1, Atg12-Atg5 and LC3-II protein expression and autophagosome formation in the sensitive SCC-15, whereas autophagy remained robust in the resistant SCC-9. Mechanistically, WWOX physically interacted with mammalian target of rapamycin (mTOR), which potentiated MTX-increased phosphorylation of mTOR and its downstream substrate p70 S6 kinase, along with dramatic downregulation of the aforementioned proteins in autophagy, in SCC-15. When WWOX was knocked down in SCC-15, MTX-induced mTOR signaling and autophagy inhibition were blocked. Thus, WWOX renders SCC cells susceptible to MTX-induced apoptosis by dampening autophagy, and the failure in inducing WWOX expression leads to chemotherapeutic drug resistance.