RESUMEN
BACKGROUND: Concurrent chemo-radiotherapy (CCRT) is the preferred non-surgical treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Unfortunately, some patients respond poorly, which leads to inappropriate or excessive treatment and affects patient survival. To accurately predict the response of ESCC patients to CCRT, we developed classification models based on the clinical, serum proteomic and radiomic data. METHODS: A total of 138 ESCC patients receiving CCRT were enrolled in this study and randomly split into a training cohort (n = 92) and a test cohort (n = 46). All patients were classified into either complete response (CR) or incomplete response (non-CR) groups according to RECIST1.1. Radiomic features were extracted by 3Dslicer. Serum proteomic data was obtained by Olink proximity extension assay. The logistic regression model with elastic-net penalty and the R-package "rms" v6.2-0 were applied to construct classification and nomogram models, respectively. The area under the receiver operating characteristic curves (AUC) was used to evaluate the predictive performance of the models. RESULTS: Seven classification models based on multi-omics data were constructed, of which Model-COR, which integrates five clinical, five serum proteomic, and seven radiomic features, achieved the best predictive performance on the test cohort (AUC = 0.8357, 95 % CI: 0.7158-0.9556). Meanwhile, patients predicted to be CR by Model-COR showed significantly longer overall survival than those predicted to be non-CR in both cohorts (Log-rank P = 0.0014 and 0.027, respectively). Furthermore, two nomogram models based on multi-omics data also performed well in predicting response to CCRT (AUC = 0.8398 and 0.8483, respectively). CONCLUSION: We developed and validated a multi-omics based classification model and two nomogram models for predicting the response of ESCC patients to CCRT, which achieved the best prediction performance by integrating clinical, serum Olink proteomic, and radiomic data. These models could be useful for personalized treatment decisions and more precise clinical radiotherapy and chemotherapy for ESCC patients.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago/terapia , Multiómica , Proteómica , Respuesta Patológica Completa , Quimioradioterapia , Estudios RetrospectivosRESUMEN
Anillin (ANLN) is a mitosis-related protein that promotes contractile ring formation and cytokinesis, but its cell cycle-dependent degradation mechanisms in cancer cells remain unclear. Here, we show that high expression of ANLN promotes cytokinesis and proliferation in esophageal squamous cell carcinoma (ESCC) cells and is associated with poor prognosis in ESCC patients. Furthermore, the findings of the study showed that the deubiquitinating enzyme USP10 interacts with ANLN and positively regulates ANLN protein levels. USP10 removes the K11- and K63-linked ubiquitin chains of ANLN through its deubiquitinase activity and prevents ANLN ubiquitin-mediated degradation. Importantly, USP10 promotes contractile ring assembly at the cytokinetic furrow as well as cytokinesis by stabilizing ANLN. Interestingly, USP10 and the E3 ubiquitin ligase APC/C co-activator Cdh1 formed a functional complex with ANLN in a non-competitive manner to balance ANLN protein levels. In addition, the macrolide compound FW-04-806 (F806), a natural compound with potential for treating ESCC, inhibited the mitosis of ESCC cells by targeting USP10 and promoting ANLN degradation. F806 selectively targeted USP10 and inhibited its catalytic activity but did not affect the binding of Cdh1 to ANLN and alters the balance of the USP10-Cdh1-ANLN complex. Additionally, USP10 expression was positively correlated with ANLN level and poor prognosis of ESCC patients. Overall, targeting the USP10-ANLN axis can effectively inhibit ESCC cell-cycle progression.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias Esofágicas/metabolismo , Proteínas Contráctiles/metabolismo , Ubiquitina/metabolismo , Proliferación Celular , Línea Celular Tumoral , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismoRESUMEN
Esophageal squamous cell carcinoma (ESCC) is one of the world's leading causes of death, and its primary clinical therapy relies on surgical resection, chemotherapy, radiotherapy, and chemoradiotherapy. Although the genomic features and clinical significance of ESCC have been identified, the outcomes of targeted therapies are still unsatisfactory. Here, we demonstrate that mitogen-activated protein kinase (MAPK) signaling is highly activated and associated with poor prognosis in patients with ESCC. Mitogen-activated protein kinase kinase (MEK) inhibitors efficiently blocked the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in ESCC, while signal transducer and activator of transcription 3 (STAT3) signaling was rapidly activated. Combined STAT3 inhibition prevented the emergence of resistance and enhanced MEK inhibitor-induced cell cycle arrest and senescence in vitro and in vivo. Mechanistic studies revealed that the suppressor of cytokine signaling 3 (SOCS3) was downregulated, resulting in an increase in STAT3 phosphorylation in MEK-inhibited cells. Furthermore, chromatin immunoprecipitation showed that ELK1, which was activated by MEK/ERK signaling, induced SOCS3 transcription. These data suggest that the development of combined MEK and STAT3 inhibition could be a useful strategy in ESCC targeted therapy.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Sistema de Señalización de MAP Quinasas , Quinasas de Proteína Quinasa Activadas por Mitógenos , Inhibidores de Proteínas Quinasas , Factor de Transcripción STAT3 , Línea Celular Tumoral , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Supresoras de la Señalización de Citocinas/metabolismoRESUMEN
Cyclophilin A (CypA) is a ubiquitous and highly conserved protein. CypA, the intracellular target protein for the immunosuppressant cyclosporine A (CsA), plays important cellular roles through peptidyl-prolyl cis-trans isomerase (PPIase). Increasing evidence shows that CypA is up-regulated in a variety of human cancers. In addition to being involved in the occurrence and development of multiple tumors, overexpression of CypA has also been shown to be strongly associated with malignant transformation. Surgery, chemotherapy and radiotherapy are the three main treatments for cancer. Chemotherapy and radiotherapy are often used as direct or adjuvant treatments for cancer. However, various side effects and resistance to both chemotherapy and radiotherapy bring great challenges to these two forms of treatment. According to recent reports, CypA can improve the chemosensitivity and/or radiosensitivity of cancers, possibly by affecting the expression of drug-resistant related proteins, cell cycle arrest and activation of the mitogen-activated protein kinase (MAPK) signaling pathways. In this review, we focus on the role of CypA in cancer, its impact on cancer chemotherapeutic and radiotherapy sensitivity, and the mechanism of action. It is suggested that CypA may be a novel potential therapeutic target for cancer chemotherapy and/or radiotherapy.
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Ciclofilina A , Neoplasias , Ciclosporina , Humanos , Inmunosupresores , Isomerasa de PeptidilprolilRESUMEN
The clinical efficacy of cisplatin in the treatment of esophageal squamous cell carcinoma (ESCC) is undesirable. Signal transducer and activator of transcription 3ß (STAT3ß), a splice variant of STAT3, restrains STAT3α activity and enhances chemosensitivity in ESCC. However, the underlying molecular mechanisms remain poorly understood. Here, we found that high expression of STAT3ß contributes to cisplatin sensitivity and enhances Gasdermin E (GSDME) dependent pyroptosis in ESCC cells after exposure to cisplatin. Mechanistically, STAT3ß was located into the mitochondria and its high expression disrupts the activity of the electron transport chain, resulting in an increase of ROS in cisplatin treatment cells. While high levels of ROS caused activation of caspase-3 and GSDME, and induced cell pyroptosis. STAT3ß blocked the phosphorylation of STAT3α S727 in mitochondria by interacting with ERK1/2 following cisplatin treatment, disrupting electron transport chain and inducing activation of GSDME. Clinically, high expression of both STAT3ß and GSDME was strongly associated with better overall survival and disease-free survival of ESCC patients. Overall, our study reveals that STAT3ß sensitizes ESCC cells to cisplatin by disrupting mitochondrial electron transport chain and enhancing pyroptosis, which demonstrates the prognostic significance of STAT3ß in ESCC therapy.
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Caspasa 3/genética , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Receptores de Estrógenos/genética , Factor de Transcripción STAT3/genética , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Transporte de Electrón/genética , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Fosforilación/efectos de los fármacos , Piroptosis/efectos de los fármacosRESUMEN
PURPOSE: Choroideremia (CHM) is an X-linked retinal degenerative disorder caused by mutations in the CHM gene. The mutations result in malfunction of the Rab escort protein 1 (REP-1). In this study, mutational analysis of the CHM gene was performed on five Chinese families clinically diagnosed with CHM. METHODS: Denaturing high performance liquid chromatography was used for mutation screening for all 15 exons and flanking intron regions of the CHM gene. Mutations were confirmed and characterized with DNA sequencing. Second samples were later collected for extraction of mRNA and proteins from leukocytes. A non-radioactive protein truncation test (PTT) was developed and used to characterize the truncating nature of the mutations. Immunoblot analysis of proteins extracted from leukocytes was also performed. RESULTS: Five mutations were identified in these five families, each with one distinct mutation: three frameshift, one nonsense, and one splicing. Two of these were novel mutations: c.627dupA in exon 5 and c.703-1G>C in intron 5. The truncating nature of the mutations was experimentally proved by PTT for four families with second samples collected. In particular, c.703-1G>C spliced exon 5 directly to exon 7 and deleted the entire exon 6 from the transcript. Direct immunoblot analysis failed to detect REP-1 in males affected by CHM, but demonstrated its presence in female carriers and homozygous normal females. CONCLUSIONS: This is the first study reporting mutations in the CHM gene in Chinese families. Mutational analysis was performed at the DNA, mRNA and protein levels. Five truncating mutations were found, and two of these were novel.
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Proteínas Adaptadoras Transductoras de Señales/genética , Pueblo Asiatico/genética , Coroideremia/genética , Mutación/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , China , Cromatografía Líquida de Alta Presión , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Humanos , Immunoblotting , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Desnaturalización de Ácido Nucleico , LinajeRESUMEN
A rapid pulsed-field gel electrophoresis (PFGE) protocol for subtyping of Streptococcus suis serotype 2 was developed and evaluated using 27 clinical isolates from 22 epidemiologically unrelated patients. Results were matched against antibiogram, virulence genotyping and multi locus sequence typing (MLST). PFGE appeared to be the most discriminatory with numerical index of discrimination (D) equal to 0.87.
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Electroforesis en Gel de Campo Pulsado/métodos , Streptococcus suis/clasificación , Animales , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Técnicas de Tipificación Bacteriana , ADN Bacteriano/análisis , Humanos , Pruebas de Sensibilidad Microbiana , Serotipificación , Streptococcus suis/efectos de los fármacos , Streptococcus suis/genética , Streptococcus suis/patogenicidad , Factores de Tiempo , Virulencia/genéticaAsunto(s)
Proteínas Bacterianas/metabolismo , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/enzimología , beta-Lactamasas/metabolismo , Anciano , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple , Enterobacteriaceae/clasificación , Enterobacteriaceae/aislamiento & purificación , Infecciones por Enterobacteriaceae/diagnóstico , Infecciones por Enterobacteriaceae/microbiología , Femenino , Hong Kong , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana EdadAsunto(s)
Infecciones por Bacterias Grampositivas/diagnóstico , Adulto , Antibacterianos/uso terapéutico , Bacterias Anaerobias , Endometriosis/complicaciones , Endometriosis/microbiología , Femenino , Bacterias Grampositivas , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Hong Kong/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Quistes Ováricos/complicaciones , Quistes Ováricos/microbiología , Resultado del Tratamiento , Vagina/microbiologíaAsunto(s)
Toxinas Bacterianas/análisis , Exotoxinas/análisis , Leucocidinas/análisis , Resistencia a la Meticilina , Staphylococcus aureus/aislamiento & purificación , Análisis de Secuencia de ADN , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidadRESUMEN
AIMS: The aim of this study was to characterise clinical and microbiological features of isolates obtained from both invasive and non-invasive Streptococcus pyogenes infections in Hong Kong, between October 2005 and April 2008. METHOD: Clinical data of invasive isolates were collected retrospectively. Altogether 281 isolates were emm sequence typed and tested for antimicrobial susceptibility using disk diffusion method. Detection of the presence of the streptococcal pyrogenic exotoxin genes was also carried out. RESULTS: emm1, emm4 and emm12 were the most prevalent in both the invasive and non-invasive groups with an increase in incidence of emm22 compared with a previous study. emm22 was associated with invasive cellulitis and wound infection. The overall rate of erythromycin resistance was 25.6% and was significantly higher in emm22 strains (85.7%). The phage-encoded superantigen gene speA was exclusively associated with emm1 in both invasive and non-invasive isolates. CONCLUSION: This study revealed a changing epidemiology of S. pyogenes infection in Hong Kong, with a unique pattern compared with other Asian countries. Invasiveness is not related to the presence of speA, speC or ssa genes and the antimicrobial resistance rate was high for macrolides. The findings have an implication on the use and efficacy of the polyvalent S. pyogenes vaccine under development.
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Farmacorresistencia Microbiana/genética , Infecciones Estreptocócicas/epidemiología , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes/aislamiento & purificación , Antibacterianos/farmacología , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas Bacterianas/genética , Farmacorresistencia Microbiana/efectos de los fármacos , Eritromicina/farmacología , Exotoxinas/genética , Genes Bacterianos/genética , Hong Kong/epidemiología , Humanos , Proteínas de la Membrana/genética , Pruebas de Sensibilidad Microbiana , Epidemiología Molecular , Estudios Retrospectivos , Infecciones Estreptocócicas/sangre , Streptococcus pyogenes/genética , Superantígenos/genéticaRESUMEN
OBJECTIVES: To characterize the genetic determinants involved in the reduced susceptibility to ciprofloxacin and cefotaxime in Salmonella enterica serotype Enteritidis clinical isolates obtained from four patients in summer 2003 in Hong Kong. METHODS: Three Salmonella Enteritidis isolates from blood culture and one from stool were collected due to their increased resistance to ciprofloxacin and cefotaxime. PFGE analysis was used to investigate their genetic relatedness. Conjugation experiments were employed to show if the genetic determinants involved were plasmid-mediated. MICs of various antimicrobials were determined by VITEK 2 and Etest. Based on the susceptibility and conjugation experiment results, previously described PCR methods were employed to detect sequences homologous to qnr and bla(CTX-M) suspected to be involved in the reduced susceptibility to ciprofloxacin and cefotaxime, respectively. RESULTS: PFGE analysis showed that the four Salmonella isolates were clonally unrelated. The presence of a qnr-like gene and the CTX-M allele bla(CTX-M-14) on four different transferable plasmids harboured by the four isolates was confirmed. CONCLUSIONS: This is the first report of transferable fluoroquinolone resistance due to a new qnr allele, which appeared to be linked to bla(CTX-M-14), in isolates of Salmonella Enteritidis in Hong Kong.
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Antibacterianos/farmacología , Cefotaxima/farmacología , Ciprofloxacina/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Salmonella enteritidis/efectos de los fármacos , Salmonella enteritidis/genética , Secuencia de Aminoácidos , Proteínas Bacterianas/genética , Conjugación Genética , Electroforesis en Gel de Campo Pulsado , Fluoroquinolonas/farmacología , Hong Kong , Humanos , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Resistencia betalactámica/genética , beta-Lactamasas/genéticaRESUMEN
Pulsed-field gel electrophoresis fingerprints of 98 Campylobacter jejuni isolates from patients (85) and chicken carcasses (13) in Hong Kong in 2002 demonstrated high genetic diversity. The prevalence of quinolone resistance among the isolates was 85.9%, and replacement of the threonine-86 residue in the gyrase subunit A was the major resistance mechanism.
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Antiinfecciosos/farmacología , Campylobacter jejuni/efectos de los fármacos , Ciprofloxacina/farmacología , Animales , Secuencia de Bases , Campylobacter jejuni/genética , Pollos/microbiología , Farmacorresistencia Bacteriana , Electroforesis en Gel de Campo Pulsado , Humanos , Pruebas de Sensibilidad Microbiana , Datos de Secuencia MolecularAsunto(s)
Infecciones por Acinetobacter/epidemiología , Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/genética , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana/genética , beta-Lactamasas/genética , Infecciones por Acinetobacter/tratamiento farmacológico , Acinetobacter baumannii/efectos de los fármacos , ADN Bacteriano/análisis , ADN Bacteriano/genética , Hong Kong/epidemiología , HumanosAsunto(s)
Antibacterianos/farmacología , Clindamicina/farmacología , Eritromicina/farmacología , Streptococcus suis/efectos de los fármacos , Tetraciclina/farmacología , Técnicas de Tipificación Bacteriana/métodos , Hong Kong , Hospitales , Humanos , Pruebas de Sensibilidad Microbiana , Serotipificación , Infecciones Estreptocócicas/microbiología , Streptococcus suis/clasificación , Streptococcus suis/aislamiento & purificaciónRESUMEN
Two hundred twenty isolates of Vibrio cholerae O1 and O139 collected from 1994 to 2002 in Hong Kong were analyzed by pulsed-field gel electrophoresis (PFGE). Chromosomal DNAs from all V. cholerae isolates in agarose plugs were digested with the restriction enzyme NotI, resulting in 20 to 27 bands. Sixty distinctive PFGE patterns in the range of 10 to 300 kb were noted among 213 isolates typeable by PFGE. By comparing the common PFGE patterns obtained from four well-defined outbreaks of V. cholerae O1 and O139 with those obtained from other, epidemiologically unrelated isolates during the study period, indistinguishable and similar PFGE patterns were identified, indicating their close relatedness, in agreement with the results of epidemiological investigations. Heterogeneous PFGE patterns (with four to six banding differences), however, were identified among strains that were imported from other parts of Asia, including Indonesia, India, and Pakistan. Correlations with epidemiological information further support the usefulness of PFGE as an epidemiological tool in laboratory investigations of suspected outbreaks. Standardization of PFGE methodology will allow international comparison of fingerprint patterns and will form the basis of a laboratory network for tracking V. cholerae.