RESUMO
The intestine is prone to radiation damage in patients undergoing radiotherapy for pelvic tumors. However, there are currently no effective drugs available for the prevention or treatment of radiation-induced enteropathy (RIE). In this study, we aimed at investigating the impact of indole-3-carboxaldehyde (I3A) derived from the intestinal microbiota on RIE. Intestinal organoids were isolated and cultivated for screening radioprotective tryptophan metabolites. A RIE model was established using 13 Gy whole-abdominal irradiation in male C57BL/6J mice. After oral administration of I3A, its radioprotective ability was assessed through the observation of survival rates, clinical scores, and pathological analysis. Intestinal stem cell survival and changes in the intestinal barrier were observed through immunofluorescence and immunohistochemistry. Subsequently, the radioprotective mechanisms of I3A was investigated through 16S rRNA and transcriptome sequencing, respectively. Finally, human colon cancer cells and organoids were cultured to assess the influence of I3A on tumor radiotherapy. I3A exhibited the most potent radioprotective effect on intestinal organoids. Oral administration of I3A treatment significantly increased the survival rate in irradiated mice, improved clinical and histological scores, mitigated mucosal damage, enhanced the proliferation and differentiation of Lgr5+ intestinal stem cells, and maintained intestinal barrier integrity. Furthermore, I3A enhanced the abundance of probiotics, and activated the AhR/IL-10/Wnt signaling pathway to promote intestinal epithelial proliferation. As a crucial tryptophan metabolite, I3A promotes intestinal epithelial cell proliferation through the AhR/IL-10/Wnt signaling pathway and upregulates the abundance of probiotics to treat RIE. Microbiota-derived I3A demonstrates potential clinical application value for the treatment of RIE.
Assuntos
Microbioma Gastrointestinal , Indóis , Camundongos Endogâmicos C57BL , Probióticos , Receptores de Hidrocarboneto Arílico , Via de Sinalização Wnt , Animais , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Humanos , Probióticos/administração & dosagem , Probióticos/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Indóis/metabolismo , Indóis/farmacologia , Protetores contra Radiação/farmacologia , Organoides/metabolismo , Lesões por Radiação/metabolismo , Lesões por Radiação/prevenção & controle , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/efeitos da radiação , Intestinos/microbiologia , Intestinos/efeitos da radiação , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genéticaRESUMO
PURPOSE: Radiation-induced intestinal injury (RIII) commonly occur during abdominal-pelvic cancer radiation therapy; however, no effective prophylactic or therapeutic agents are available to manage RIII currently. This study aimed to clarify the potential of probiotic consortium supplementation in alleviating RIII. METHODS AND MATERIALS: Male C57BL/6J mice were orally administered a probiotic mixture comprising Bifidobacterium longum BL21, Lactobacillus paracasei LC86, and Lactobacillus plantarum Lp90 for 30 days before exposure to 13 Gy of whole abdominal irradiation. The survival rates, clinical scores, and histologic changes in the intestines of mice were assessed. The impacts of probiotic consortium treatment on intestinal stem cell proliferation, differentiation, and epithelial barrier function; oxidative stress; and inflammatory cytokines were evaluated. A comprehensive examination of the gut microbiota composition was conducted through 16S rRNA sequencing, while changes in metabolites were identified using liquid chromatography-mass spectrometry. RESULTS: The probiotic consortium alleviated RIII, as reflected by increased survival rates, improved clinical scores, and mitigated mucosal injury. The probiotic consortium treatment exhibited enhanced therapeutic effects at the histologic level compared with individual probiotic strains, although there was no corresponding improvement in survival rates and colon length. Moreover, the probiotic consortium stimulated intestinal stem cell proliferation and differentiation, enhanced the integrity of the intestinal epithelial barrier, and regulated redox imbalance and inflammatory responses in irradiated mice. Notably, the treatment induced a restructuring of the gut microbiota composition, particularly enriching short-chain fatty acid-producing bacteria. Metabolomic analysis revealed distinctive metabolic changes associated with the probiotic consortium, including elevated levels of anti-inflammatory and antiradiation metabolites. CONCLUSIONS: The probiotic consortium attenuated RIII by modulating the gut microbiota and metabolites, improving inflammatory symptoms, and regulating oxidative stress. These findings provide new insights into the maintenance of intestinal health with probiotic consortium supplementation and will facilitate the development of probiotic-based therapeutic strategies for RIII in clinical practice.
Assuntos
Microbioma Gastrointestinal , Homeostase , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Probióticos , Animais , Probióticos/farmacologia , Probióticos/uso terapêutico , Masculino , Camundongos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos da radiação , Mucosa Intestinal/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Lesões por Radiação/prevenção & controle , Lesões por Radiação/patologia , Proliferação de Células/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Intestinos/microbiologia , Diferenciação Celular/efeitos dos fármacos , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/metabolismo , Células-Tronco , Citocinas/metabolismoRESUMO
The small intestine exhibits remarkable sensitivity to ionizing radiation (IR), which significantly hampers the effectiveness of radiotherapy in the treatment of abdominal and pelvic tumors. Unfortunately, no effective medications are available to treat radiation-induced intestinal damage (RIID). Fraxin (7-hydroxy-6-methoxycoumarin 8-glucoside), is a coumarin derivative extracted from the Chinese herb Cortex Fraxini. Several studies have underscored the anti-inflammatory, antibacterial, antioxidant, and immunomodulatory properties of fraxin. However, the efficacy of fraxin at preventing or mitigating RIID remains unclear. Thus, the present study aimed to investigate the protective effects of fraxin against RIID in vitro and in vivo and to elucidate the underlying mechanisms. The study findings revealed that fraxin markedly ameliorated intestinal injuries induced by 13 Gy whole abdominal irradiation (WAI), which was accompanied by a significant increase in the population of Lgr5+ intestinal stem cells (ISCs) and Ki67+ progeny. Furthermore, fraxin mitigated WAI-induced intestinal barrier damage, and reduced oxidative stress and intestinal inflammation in mice. Transcriptome sequencing of fraxin-treated mice revealed upregulation of IL-22, a pleiotropic cytokine involved in regulating the function of intestinal epithelial cells. Moreover, in both human intestinal epithelial cells and ex vivo cultured mouse intestinal organoids, fraxin effectively ameliorated IR-induced damage by promoting the expression of IL-22. The radioprotective effects of fraxin were partially negated in the presence of an IL-22-neutralizing antibody. In summary, fraxin is demonstrated to possess the ability to alleviate RIID and maintain intestinal homeostasis, suggesting that fraxin might serve as a strategy for mitigating accidental radiation exposure- or radiotherapy-induced RIID.
Assuntos
Cumarínicos , Intestinos , Camundongos , Humanos , Animais , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Antioxidantes , Radiação IonizanteRESUMO
PURPOSE: In this study, we aimed to compare the radiation-induced hepatic toxicity (RIHT) outcomes of radiotherapy (RT) plus antibodies against programmed cell death protein 1 (anti-PD1) versus RT alone in patients with hepatocellular carcinoma (HCC), evaluate prognostic factors of non-classic radiation-induced liver disease (ncRILD), and establish a nomogram for predicting the probability of ncRILD. PATIENTS AND METHODS: Patients with unresectable HCC treated with RT and anti-PD1 (RT + PD1, n = 30) or RT alone (n = 66) were enrolled retrospectively. Patients (n = 30) in each group were placed in a matched cohort using propensity score matching (PSM). Treatment-related hepatotoxicity was evaluated and analyzed before and after PSM. The prognostic factors affecting ncRILD were identified by univariable logistic analysis and Spearman's rank test in the matched cohort to generate a nomogram. RESULTS: There were no differences in RIHT except for increased aspartate aminotransferase (AST) ≥ grade 1 and increased total bilirubin ≥ grade 1 between the two groups before PSM. After PSM, AST ≥ grade 1 occurred more frequently in the RT + PD1 group (p = 0.020), and there were no significant differences in other hepatotoxicity metrics between the two groups. In the matched cohort, V25, tumor number, age, and prothrombin time (PT) were the optimal prognostic factors for ncRILD modeling. A nomogram revealed a good predictive performance (area under the curve = 0.82). CONCLUSIONS: The incidence of RIHT in patients with HCC treated with RT + PD1 was acceptable and similar to that of RT treatment. The nomogram based on V25, tumor number, age, and PT robustly predicted the probability of ncRILD.
Assuntos
Carcinoma Hepatocelular , Doença Hepática Induzida por Substâncias e Drogas , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , Receptor de Morte Celular Programada 1 , Pontuação de PropensãoRESUMO
BACKGROUND: The incidence of classic radiation-induced liver disease (cRILD) has been significantly reduced. However, non-classic radiation-induced liver disease (ncRILD) remains a major concern following radiotherapy in patients with hepatocellular carcinoma (HCC). This study evaluated the incidence of ncRILD following intensity-modulated radiotherapy (IMRT) for Child-Pugh grade B (CP-B) patients with locally advanced HCC and established a nomogram for predicting ncRILD probability. METHODS: Seventy-five CP-B patients with locally advanced HCC treated with IMRT between September 2014 and July 2021 were included. The max tumor size was 8.39 cm ± 5.06, and the median prescribed dose was 53.24 Gy ± 7.26. Treatment-related hepatotoxicity was evaluated within three months of completing IMRT. A nomogram model was formulated to predict the probability of ncRILD, using univariate and multivariate analysis. RESULTS: Among CP-B patients with locally advanced HCC, ncRILD occurred in 17 (22.7%) patients. Two patients (2.7%) exhibited a transaminase elevation of ≥ G3, fourteen (18.7%) exhibited a Child-Pugh score increase of ≥ 2, and one (1.3%) demonstrated both a transaminase elevation of ≥ G3 and a Child-Pugh score increase of ≥ 2. No cRILD cases were observed. A mean dose to the normal liver of ≥ 15.1 Gy was used as the cutoff for ncRILD. Multivariate analysis revealed that the prothrombin time before IMRT, tumour number, and mean dose to the normal liver were independent risk factors for ncRILD. The nomogram established on the basis of these risk factors displayed exceptional predictive performance (AUC = 0.800, 95% CI 0.674-0.926). CONCLUSIONS: The incidence of ncRILD following IMRT for CP-B patients with locally advanced HCC was acceptable. A nomogram based on prothrombin time before IMRT, tumour number, and mean dose to the normal liver accurately predicted the probability of ncRILD in these patients.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Lesões por Radiação , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/complicações , Radioterapia de Intensidade Modulada/efeitos adversos , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/complicações , Lesões por Radiação/epidemiologia , Lesões por Radiação/etiologia , Transaminases , Dosagem RadioterapêuticaRESUMO
BACKGROUND: The combination of transcatheter arterial chemoembolization (TACE) plus sorafenib prolonged progression-free survival (PFS) and overall survival (OS) than sorafenib or TACE monotherapy for patients with hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of radiotherapy (RT) plus monoclonal antibody against programmed cell death 1 (anti-PD1) versus TACE plus sorafenib for patients with advanced HCC. METHODS: Patients with advanced HCC who treated with RT plus anti-PD1 and TACE plus sorafenib were enrolled. Objective response rate (ORR), PFS, disease control rate (DCR) and OS were calculated to assess the antitumor response and the treatment-related adverse events to the safety. RESULTS: Between January 2018 to March 2021, 37 patients underwent RT plus anti-PD1 and 41 patients underwent TACE plus sorafenib. The baseline characteristics between the two groups were comparable. The ORR and DCR were significantly higher in the RT + PD1 group than the TACE plus sorafenib group according to RECIST 1.1 (54.05% vs. 12.20%, P < 0.001; 70.27% vs. 46.37%, P = 0.041; respectively) and according to mRECIST (56.76% vs. 31.71%, P = 0.039; 70.27% vs. 46.37%, P = 0.041; respectively). RT plus anti-PD1 provided significantly better PFS (HR, 0.51; 95% CI 0.30-0.86; P = 0.017) than TACE plus sorafenib. Moreover, patients with RT plus anti-PD1 had significantly higher 3-, 6-, and 9-month OS rates than those with TACE plus sorafenib(97.3% vs. 92.30%, P < 0.001; 91.89% vs. 68.60%, P < 0.001; 75.5% vs. 60.60%, P < 0.001; respectively). The median OS was more favorable 17.4 months for the RT + PD1 group and 11.9 months for the TACE plus sorafenib group. No treatment-related death was observed. Grade 3 or more treatment-related adverse events (TRAEs) occurred significantly less in patients in the RT + PD1 group than the TACE plus sorafenib group (29.7% vs. 75.6%, P < 0.001), and all TRAEs were manageable. CONCLUSIONS: In this real-world study, RT plus anti-PD1 showed significantly promising efficacy and manageable safety than TACE plus sorafenib in patients with advanced HCC. Toxicities were manageable, with no unexpected safety signals. The study provides evidence on a new therapeutic method in the treatment of advanced HCC.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Terapia Combinada , Humanos , Neoplasias Hepáticas/patologia , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Sorafenibe/uso terapêuticoRESUMO
This study aimed to investigate the anti-inflammatory effect of astragaloside â £ in mice with ulcerative colitis(UC) and its effect on the percentage of peripheral blood T helper(Th17) cells. Following the establishment of UC mouse model with 2% sodium dextran sulfate(DSS), mice in the positive control group and low-and high-dose astragaloside â £ groups were treated with corresponding drugs by gavage. Disease activity index(DAI) was calculated, and serum interleukin-17(IL-17), tumor necrosis factor-α(TNF-α), and transforming growth factor-ß(TGF-ß) levels were assayed by ELISA. The pathological changes in colon tissue were observed by HE staining, and Th17/regulatory T cells(Treg) ratio in the peripheral blood was determined by flow cytometry. Western blot was conducted for detecting the relative protein expression levels of forkhead box protein P3(Foxp3) and retinoic acid-related orphan nuclear receptor γT(ROR-γt). The findings demonstrated that in normal mice, the colonic structure was intact. The goblet cells were not reduced and the glands were neatly arranged, with no mucosal erosion, bleeding, or positive cell infiltration. In the model group, the colonic mucosal structure was seriously damaged, manifested as disordered arrangement or missing of glands, vascular dilatation, congestion, and massive inflammatory cell infiltration. The pathological injury of colon tissue was alleviated to varying degrees in drug treatment groups. Compared with the normal group, the model group exhibited elevated percentage of Th17 cells, increased IL-17 and TNF-α content, up-regulated relative ROR-γt protein expression, lowered TGF-ß, reduced percentage of Treg cells, and down-regulated relative Foxp3 protein expression. The comparison with the model group showed that DAI score, pathological score, percentage of Th17 cells, IL-17 and TNF-α content, and relative ROR-γt protein expression in the positive control group, low-dose astragaloside â £ group, and high-dose astragaloside â £ group were decreased, while TGF-ß content, percentage of Treg cells, and relative Foxp3 protein expression were increased. The DAI score, pathological score, percentage of Th17 cells, IL-17 and TNF-α content, and relative ROR-γt protein expression in the low-dose astragaloside â £ group were higher than those in the positive control group, whereas the content of TGF-ß, percentage of Treg cells, and relative Foxp3 protein expression were lower. DAI score, pathological score, percentage of Th17 cells, IL-17 and TNF-α content, relative ROR-γt protein expression in the high-dose astragaloside â £ group declined in contrast to those in the low-dose astragaloside â £ group, while the TGF-ß content, percentage of Treg cells, and relative Foxp3 protein expression rose. There was no significant difference between the positive control group and the high-dose astragaloside â £ group. Astragaloside â £ is able to inhibit inflammatory response and diminish the percentage of Th17 cells in mice with UC.
Assuntos
Colite Ulcerativa , Saponinas , Triterpenos , Animais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Camundongos , Saponinas/farmacologia , Linfócitos T Reguladores , Células Th17 , Triterpenos/farmacologiaRESUMO
The coexistence of lung cancer and pulmonary tuberculosis (PTB) is uncommon in young patients. We report a case of 22-year-old man who presented with a one-month history of chest pain, cough, slight haemoptysis and weight loss. Following two acid fast bacilli positive sputum samples, a diagnosis of TB was concluded. However, his response to anti-TB therapy was inadequate. A CT scan and further laboratory tests assisted the final diagnosis as c-ros oncogene 1 (ROS1) rearranged lung adenocarcinoma and PTB. Despite severe comorbidities, the patient achieved clinical remission following treatment with the anti-cancer drug, crizotinib and anti- TB therapy. Clinicians should be aware that this comorbidity can occur in all age groups and the clinical and radiological symptoms of the two diseases are similar.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Tuberculose Pulmonar , Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/tratamento farmacológico , Adulto , Estado Terminal , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Oncogenes , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/tratamento farmacológico , Adulto JovemRESUMO
Human leucocyte antigen (HLA)-G has seven isoforms, of which HLA-G1-G4 are membrane-bound and HLA-G5-G7 are soluble. Previous studies reinforced HLA-G expression was strongly related to poor prognosis in different types of cancers. Among these studies, the monoclonal antibody (mAb) 4H84 was used which detects all HLA-G isoform heavy chain; unfortunately, leaves the specific types of isoforms expressed in lesions undistinguished and its clinical significance needs to be clarified. To explore clinical significance of lesion soluble HLA-G (sHLA-G) in non-small-cell lung cancer (NSCLC), mAb 5A6G7 recognizing HLA-G5/-G6 molecules was used. Tumour cell sHLA-G expression in 131 primary NSCLC lesions (66 squamous cell carcinoma, 55 adenocarcinoma and 10 adenosquamous carcinoma) were analysed with immunohistochemistry. Data showed that sHLA-G expression was observed in 34.0% (45/131) of the NSCLC lesions, which was unrelated to patient age, sex, lymph nodal status, tumour-node-metastasis stage and patient survival. However, tumour cell sHLA-G expression in lesions was predominately observed in adenocarcinoma lesions (73.0%, 40/55) which was significantly higher than that in squamous cell carcinoma (6.0%, 4/66) and adenosquamous carcinoma lesions (10.0%, 1/10, P < 0.001). The area under the receiver operating characteristic curve for lesion sHLA-G was 0.833 (95% CI: 0.754-0.912, P < 0.001) for adenocarcinoma versus squamous cell carcinoma. Our findings for the first time showed that tumour cell sHLA-G was predominately expressed in lung adenocarcinoma, which could be a useful biomarker to discriminate adenocarcinoma from squamous cell carcinoma in NSCLC patients.
Assuntos
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Antígenos HLA-G/biossíntese , Neoplasias Pulmonares/metabolismo , Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/biossíntese , Western Blotting , Carcinoma Adenoescamoso/diagnóstico , Carcinoma Adenoescamoso/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Diagnóstico Diferencial , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica/métodos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Isoformas de Proteínas/biossíntese , Curva ROCRESUMO
OBJECTIVE: To investigate effects of mandibular advancement device (MAD) therapy for obstructive sleep apnoea hypopnea syndrome (OSAHS) on the genioglossus contractile properties and fibre-type distribution. MATERIALS AND METHODS: Thirty 6-month old male New Zealand white rabbits were randomised into three groups: OSAHS, MAD, and controls. Rabbits in Group OSAHS and Group MAD were established as OSAHS models by injection, at a dose of 2 ml hydrophilic polyacrylamide gel, via the submucous muscular layer of soft palate. Spiral computed tomography (CT) showed a significant reduced retropalatal upper airway, and apnoeas happened with an increase of Apnea Hypopnea Index (AHI) and a decrease of blood oxygen saturation during polysomnography (PSG), which indicated the OSAHS model developed successfully. OSAHS rabbits in Group MAD were fitted with a MAD made from self-curing composite resin, at 30 degrees to the upper incisors, and the mandible was guided forward 3 to 4mm. Further, spiral CT and PSG suggested MAD was effective. Rabbits in 3 groups were induced to sleep for 4-6 hours per day for 8 weeks, after which the genioglossus was removed, mounted in a tissue bath, and stimulated through platinum electrodes; maximal twitch tension, contraction time, half-relaxation time, force-frequency relationship, and fatigability were recorded. The percentage of Type I and Type II fibres was quantified. RESULTS: The fatigability and percentage of Type II fibres of genioglossus increased in Group OSAHS compared with controls; this abnormality was corrected by MAD. CONCLUSION: MAD therapy for OSAHS could prevent genioglossus fatigue and abnormal fibre-type distribution of genioglossus in OSAHS.
Assuntos
Avanço Mandibular/instrumentação , Aparelhos Ortodônticos , Apneia Obstrutiva do Sono/terapia , Língua/patologia , Resinas Acrílicas/administração & dosagem , Adenosina Trifosfatases/análise , Animais , Modelos Animais de Doenças , Estimulação Elétrica , Injeções , Masculino , Contração Muscular/fisiologia , Fadiga Muscular/fisiologia , Fibras Musculares de Contração Rápida/patologia , Fibras Musculares de Contração Rápida/fisiologia , Tono Muscular/fisiologia , Oxigênio/sangue , Palato Mole/efeitos dos fármacos , Palato Mole/patologia , Polissonografia/métodos , Coelhos , Distribuição Aleatória , Tomografia Computadorizada Espiral/métodos , Língua/fisiopatologiaRESUMO
Protein phosphatase, Mg2+/Mn2+ dependent, 1D (PPM1D) has been associated with carcinogenesis. The present study investigated PPM1D expression as a potential biomarker in colorectal cancer (CRC). PPM1D expression was assessed using immunohistochemistry in 368 patients with CRC. The correlation between PPM1D expression, clinicopathological features and prognosis was analyzed. PPM1D small interfering (si)RNA-induced PPM1D silencing was performed in CRC cell lines to assess the effect of PPM1D on tumor cell proliferation and invasion in vitro. A total of 68.48% (252/368) of the CRC samples displayed high PPM1D expression. By contrast, only 9.24% (34/368) of the matched non-cancerous tissue samples exhibited high PPM1D expression. High PPM1D expression was correlated with node metastasis (P=0.0024), distant metastasis (P<0.001) and TNM stage (P=0.0016). Kaplan-Meier survival analysis revealed that patients with low PPM1D expression had significantly longer survival than those with high PPM1D expression (P=0.012). Moreover, multivariate analyses demonstrated that high PPM1D expression was an independent prognostic factor for overall survival (hazard ratio = 0.24; 95% confidence interval, 0.13-0.86; P=0.004). Furthermore, PPM1D gene silencing was found to significantly reduce the proliferation and invasion of CRC cells in vitro. These findings suggest a role for PPM1D as a prognostic marker and potential therapeutic target in CRC.
RESUMO
Paclitaxel, a known TLR4 ligand, leads to activation of TLR4/MyD88-dependent pathway that mediates chemoresistance and tumor progression in epithelial ovarian carcinoma (EOC). Atractylenolide-I (AO-I), a novel TLR4-antagonizing agent, inhibits TLR4 signaling by interfering with the binding of LPS or paclitaxel to membrane TLR4 of human leukocytes. In this study, AO-I was found to attenuate paclitaxel-induced protein expression of IL-6, VEGF and survivin, and to enhance early apoptosis and growth inhibition in MyD88(+) EOC cells; AO-I was shown to fit into the hydrophobic pocket of human MD-2 and to partially overlap with the binding site of paclitaxel by docking simulations, suggesting that AO-I may block the MD-2-mediated TLR4/MyD88-dependent paclitaxel signaling in MyD88(+) EOC cells. Therefore, AO-I could significantly sensitize the response of MyD88(+) EOC cells to paclitaxel by blocking MD-2-mediated TLR4/MyD88 signaling, and that AO-I-paclitaxel combination could be a promising strategy for the treatment of EOC with a functional TLR4/MyD88/NF-κB pathway.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lactonas/farmacologia , Antígeno 96 de Linfócito/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Sesquiterpenos/farmacologia , Receptor 4 Toll-Like/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Epitelial do Ovário , Proliferação de Células/efeitos dos fármacos , Antagonistas Colinérgicos/farmacologia , Sinergismo Farmacológico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-6/metabolismo , Antígeno 96 de Linfócito/química , Antígeno 96 de Linfócito/genética , Simulação de Acoplamento Molecular , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Conformação Proteica , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Células Tumorais CultivadasRESUMO
A new fluorescent chemosensor based on a helical imide as fluorophore and a cyclen moiety as ionophore was synthesized, which not only showed enhanced fluorescent responses in the presence of Zn(2+), Cd(2+), and Hg(2+) but also could simultaneously and selectively distinguish the three cations in a simulated physiological condition with the help of cysteine as an auxiliary reagent.
Assuntos
Cádmio/análise , Cádmio/química , Cátions/química , Corantes Fluorescentes/química , Mercúrio/análise , Mercúrio/química , Água/química , Zinco/análise , Zinco/química , Estrutura Molecular , Espectrometria de FluorescênciaRESUMO
Eight new acyclic manoalide-related sesterterpenes, hippolides A-H (1-8), together with two known manoalide derivatives, (6E)-neomanoalide (9) and (6Z)-neomanoalide (10), were isolated from the South China Sea sponge Hippospongia lachne. The absolute configurations of 1-8 were established by the modified Mosher's method and CD data. Compound 1 exhibited cytotoxicity against A549, HeLa, and HCT-116 cell lines with IC50 values of 5.22×10(-2), 4.80×10(-2), and 9.78 µM, respectively. Compound 1 also showed moderate PTP1B inhibitory activitiy with an IC50 value of 23.81 µM, and compound 2 showed moderate cytotoxicity against the HCT-116 cell line and PTP1B inhibitory activity with IC50 values of 35.13 and 39.67 µM, respectively. In addition, compounds 1 and 5 showed weak anti-inflammatory activity, with IC50 values of 61.97 and 40.35 µM for PKCγ and PKCα, respectively.
Assuntos
Anti-Inflamatórios não Esteroides/isolamento & purificação , Antineoplásicos/isolamento & purificação , Poríferos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Sesterterpenos/isolamento & purificação , Terpenos/isolamento & purificação , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , China , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HeLa , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Sesterterpenos/química , Sesterterpenos/farmacologia , Terpenos/química , Terpenos/farmacologiaRESUMO
This study was aimed to investigate the expression and clinical significance of CDX1, CDX2 and CDX4 genes in acute lymphocytic leukemia (ALL). Expressions of CDX1, CDX2, and CDX4 in 51 adult acute lymphocytic leukemia patients and 14 healthy subjects were detected by reverse transcription polymerase chain reaction (RT-PCR). The results indicated that CDX1, CDX2 and CDX4 were not expressed in 14 healthy persons and 15 CR ALL patients, the positive expression rate of CDX2 gene in de novo ALL patients was 60.8%, while it obviously decreased in patients with complete remission (CR) (p < 0.05); the expression of CDX2 was increased again in relapsed patients (81.8%). When the expression of CDX2 was analyzed in different risk groups of ALL patients, the CDX2 expression rate in high risk (HR) patients was 91.7%, and that in the standard risk (SR) group was 45.7%. Furthermore, analyses of CDX1 and CDX4 expression in series of ALL samples did not show the expression of these genes. In patients with adult ALL at diagnosis and relapse, the CR rate of patients with CDX2 positive expression was lower than that of patients with CDX2 negative expression (p < 0.05). The median survival time in CDX2 positive expression patients was shorter than that in negative expression patient. It is concluded that expression of CDX2 may correlated with pathogenesis and relapse of adult ALL, but the expression of CDX1 and CDX4 don' t associated with pathogenesis and relapse of adult ALL; the CR rate and prognosis of patients with CDX2 positive expression is lower and poor. The expression of CDX2 may be used as a marker for occurrence, relapse and poor prognosis of adult ALL patients.
Assuntos
Genes Homeobox , Proteínas de Homeodomínio/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Idoso , Fator de Transcrição CDX2 , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: To study clinical efficacy on cesarean scar pregnancy (CSP) treated by transvaginal surgery. METHODS: From Jan. 2008 to Mar. 2011, 31 cases with CSP were managed by transvaginal surgery in Anshan Women and Children Hospital. Based on ultrasonograpy examination and intraoperative exposure of lesion, variable surgical options were executed. Fifteen cases in group A were treated by debridement resection and vaginal repair of uterine wall, 7 cases in group B were treated by transvaginal uterine artery ligation and curettage, 9 cases were treated by cutting the anterior wall in the lower uterine segment and repairing uterine. The intraoperative blood loss, operation time, hospital stay, hCG fluctuation at postoperative period and complications were analyzed among those groups. RESULTS: All cases in 3 groups were cured well in one time. (1) The intraoperative blood loss were (41 ± 21) ml in group A, (27 ± 7) ml in group B and (148 ± 132) ml in group C. There was no statistically different blood loss between group A and group B (P > 0.05), however, the amount blood loss in group C was significantly more than those in group A and group B (P < 0.05). (2) The average surgical time, the mean hospital stay, postoperative recovery time of blood hCG were (40 ± 11) minutes, (4.7 ± 0.8) days and (2.7 ± 1.0) weeks in group A, (44 ± 5) minutes, (4.0 ± 0.8) days and (2.9 ± 1.0) weeks in group B, (40 ± 12) minutes, (4.9 ± 1.0) days and (2.8 ± 0.9) weeks in group C. Those clinical index were no statistically different among those 3 groups (P > 0.05). (3) No bladder injury and other complications were observed in those groups. CONCLUSIONS: Transvaginal surgery is efficacy, easy to operate, to keep the uterus, safe and economy in treatment of CSP. Surgery in group A is suitable to treat early and exogenous lesions; surgery in group B is suitable to treat endogenous lesions; surgery in group C is suitable to treat failure cases in group A and B, however, the injury is greater than those in group A and B.
Assuntos
Cesárea/efeitos adversos , Cicatriz/complicações , Embolização da Artéria Uterina , Perda Sanguínea Cirúrgica , Gonadotropina Coriônica Humana Subunidade beta/sangue , Cicatriz/diagnóstico por imagem , Cicatriz/cirurgia , Curetagem , Feminino , Humanos , Tempo de Internação , Duração da Cirurgia , Complicações Pós-Operatórias , Gravidez , Gravidez Ectópica , Estudos Retrospectivos , Resultado do Tratamento , Ultrassonografia , Artéria Uterina/cirurgia , Útero/irrigação sanguínea , Útero/diagnóstico por imagem , Útero/cirurgia , CicatrizaçãoRESUMO
OBJECTIVE: To investigate whether whole tumor cell vaccination strategies in combination with bone marrow transplantation (BMT) can stimulate graft-versus-tumor effect (GVT). METHODS: Twenty-six BALB/c mice were randomly divided into 3 groups: BMT group (group A, n = 10), BMT + vaccination group (group B, n = 10), control group (group C, n = 6). (BALB/c × C57BL/6) F1 mice [CB6F1, H-2K(b/d)] were used as donors. BALB/c mice of group C were only inoculated with Renca cell (2.6 × 10(6)). Mice of group A and B were conditioned with 8 Gy irradiation, followed by infusion by bone marrow cell of CB6F1 mice on day 1, then inoculated with Renca cell (2.6 × 10(6)) on day 8. All mice of group B were immunized subcutaneous on the back with 5 × 10(5) irradiated Renca tumor cells on day 9 and day 16. All mice of group C were inoculated with Renca cell (2.6 × 10(6)) on day 8. In group A and B, all mice were analyzed by fluorescence activated cell sorter (FACS) on day 14, and 28 day after BMT. Mice were killed on day 32 after inoculation with tumor cell and collected blood sample. All tumors were taken out to be weighed and then fixed in 10% buffered formalin, embedded in paraffin, and cut into 5 µm slices. The slices were stained with HE and examined by TdT mediated-dUTP nick end labeling (TUNEL). Liver, skin, intestine, and spleen were biopsied for histopathological examination. RESULTS: The results of chimera showed that engraftments of group A, B were full donor chimerism, and the chimerism of those remained above 90% and preserved even after 28 days. The tumor weight, tumor volume increment in the group B was lower than group A and C (P < 0.05). The tumor suppressing rates of the group A and B were 54%, 60% respectively. The area ratio of tumor necrosis and apoptosis index (AI) of the tumor in the group B were higher than group A and C (P < 0.05). Graft-versus-host disease was not observed in each group. CONCLUSION: The mechanism of GVT after haploidentical allogeneic bone marrow transplantation with tumor vaccination may be the promotion of tumor necrosis and apoptosis.
Assuntos
Transplante de Medula Óssea/imunologia , Vacinas Anticâncer/imunologia , Efeito Enxerto vs Tumor/imunologia , Neoplasias Renais/terapia , Animais , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Células Cultivadas , Modelos Animais de Doenças , Neoplasias Renais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Quimeras de Transplante/imunologiaRESUMO
Pentiptycene-based mono(crown ether)s and tetracationic cyclobis(paraquat-p-phenylene) can form 1 : 1 stable complexes in solution and in the solid state, in which both of the components act as the host as well as the guest.
Assuntos
Antracenos/química , Éteres de Coroa/química , Paraquat/análogos & derivados , Paraquat/química , Cátions/química , Estrutura Molecular , Soluções , EstereoisomerismoRESUMO
OBJECTIVE: To investigate the effect of cytosine deaminase (CD) gene plus 5-fluorocytosine (5-Fc) on the growth of human colon cancer xenograftin nude mice. METHODS: Retroviral vector expressing CD gene was transfected into human colon cancer SW1116 cells. Expression of the transfected CD gene in SW1116 (SWCD(2)) was confirmed by RT-PCR. The cytotoxicity of 5-Fc on SW1116 was determined by MTT assay in vitro. In vivo, the CD gene expression vector was injected intratumorally and 5-Fc was given by ip injections. RESULTS: In vitro, SWCD(2) cells were killed by 5-Fc with an IC(50) of 66 micromol/L while the nontrasfected SW1116 cells needed an IC(50) of 16 000 micromol/L to be killed. The growth of SWCD(2) xenografts was significantly inhibited by systemic administration of 5-Fc. CONCLUSION: CD gene/5-Fc system is a potential gene therapy strategy for human colon cancer.
Assuntos
Neoplasias do Colo/prevenção & controle , Citosina Desaminase/genética , Flucitosina/uso terapêutico , Terapia Genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Terapia Combinada , Citosina Desaminase/metabolismo , Feminino , Flucitosina/farmacologia , Vetores Genéticos , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Retroviridae/genética , TransfecçãoRESUMO
BACKGROUND & OBJECTIVE: Gemcitabine (2',2-difluorodeo- xycytide) has antitumor activity in both experimental and clinical treatment of solid tumors. Although resistance to gemcitabine in ovarian cancer cell line and erythroleukemic cell line was described, there was no report on the lung cancer resistant variant. In order to elucidate the mechanism by which gemcitabine induce resistance in lung cancer, we have established the resistance to gemcitabine in human lung adenocarcinoma cell line A549 and described the characteristics of its resistant variant. METHODS: Resistance to gemcitabine was established by exposing A549 cells to increasing concentration of gemcitabine, which was designated as A549-Gem. The IC(50) and resistance index(RI) were tested by MTT assay and colony formation test. The growth curve and cell cycle of A549 and A549-Gem were compared. The cross-resistance profile of A549-Gem was also tested. RESULTS: The IC(50) increased from 6.56+/-1.19 micromol/L in A549 to 921.09+/-225.27 micromol/L in A549-Gem as tested by MTT assay at 72h exposure, the RI was 140.52 (P=0.019 5). The RI of colony formation test was 132.95. Double time of A549 and A549-Gem were 29.7 h and 36.4 h, respectively, as evaluated by the growth curve. A549-Gem was cross-resistant to vincristine and etoposide(54.38-fold and 6.18-fold)(P< 0.01), but not to adriamycin, cisplatin, cytarabine, and paclitaxel. CONCLUSION: A549-Gem, the gemcitabine resistant phenotype, is stable and suitable for the study of gemcitabine resistance in lung cancer. A549-Gem is cross-resistant to vincristine and etoposide, but not resistant to adriamycin, cisplatin, cytarabine and paclitaxel.