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Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.
Assuntos
Linfócitos T CD8-Positivos , Serotonina , Linfócitos T CD8-Positivos/metabolismo , Serotonina/metabolismo , Serotonina/farmacologia , Processamento de Proteína Pós-Traducional , Transdução de SinaisRESUMO
BACKGROUND: Circulating long noncoding RNAs (lncRNAs) are considered a new class of biomarkers for the diagnosis and prognosis of various malignancies. We aimed to identify circulating lncRNAs as biomarkers for the diagnosis and prognosis of non-small cell lung cancer (NSCLC). METHODS: The expression of 14 candidate lncRNAs was measured in matched cancer and ipsilateral normal lung tissues of 20 patients with NSCLC using quantitative reverse-transcription PCR. In plasma samples from training and testing sets, significantly and aberrantly expressed lncRNAs, TA73-AS1 and CRNDE, were further analyzed. Receiver operating characteristic (ROC) curves were constructed, and the areas under the ROC curves (AUC) were obtained to assess diagnostic performance. The Kaplan-Meier survival analysis was used to assess the impact of plasma TA73-AS1 and CRNDE expression on tumor-free survival (TFS) of patients with NSCLC. The effect of TP73-AS1 expression on NSCLC cells was investigated in vitro. RESULTS: AUC values of plasma TA73-AS1 and CRNDE were 0.822 and 0.815 in the training set and 0.843 and 0.804 in the testing set, respectively, to distinguish NSCLC from healthy controls. The combination of plasma TP73-AS1, CRNDE, and two classical tumor markers, carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1), showed excellent diagnostic performance for NSCLC (AUC =0.927 in the training set; AUC = 0.925 in the testing set). Furthermore, the high expression of the two plasma lncRNAs correlated with worse TFS in patients with NSCLC. In vitro cell model studies revealed that TP73-AS1 overexpression facilitated NSCLC cell survival, invasion, and migration. CONCLUSION: Circulating TP73-AS1 and CRNDE could be potential biomarkers for the diagnosis and prognostic prediction of NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Prognóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Biomarcadores Tumorais , Regulação Neoplásica da Expressão GênicaRESUMO
Resistance to epidermal growth factor receptor-tyrosin kinase inhibitors (TKIs, e.g. icotinib) remains a major clinical challenge. Non-small cell lung cancer patients with wild-type EGFR and/or K-RAS mutation are primary resistance to EGFR-TKIs. Berberine has been found to have potent anticancer activities via distinct molecular mechanism. In this study, we sought to investigate the therapeutic utility of BBR in combination with icotinib to overcome icotinib resistance in NSCLC cells, and explore the molecular mechanism of synergism of icotinib and BBR to EGFR-resistant NSCLC cells. We used the two EGFR-resistant NSCLC cell lines H460 and H1299 for testing the inhibitory effect of icotinib and/or BBR on them. Moreover, xenograft mouse model was applied for assessing the anti-tumor activities of BBR and icotinib in combination. Results showed that BBR and icotinib have a synergistic inhibitory effect on H460 and H1299 cells through induction of autophagic cell death and apoptosis. Accordingly, the anti-cancer effect of BBR plus icotinib was further confirmed in the NSCLC xenograft mouse models. Combination of BBR and icotinib significantly inhibited the protein expression and the activity of EGFR by inducing autophagic EGFR degradation. BBR plus icotinib resulted in intracellular ROS accumulation, which could mediated autophagy and apoptosis and involved in the suppression of cell migration and invasion. In conclusions, combination application of BBR and icotinib could be an effective strategy to overcome icotinib resistance in the treatment of NSCLC.
Assuntos
Morte Celular Autofágica , Berberina , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Apoptose , Berberina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Éteres de Coroa , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Quinazolinas , Transdução de SinaisRESUMO
Previous studies have reported that the aberrant expression of circulating microRNAs (miRNAs/miRs) can be used as diagnostic and prognostic markers in non-small cell lung cancer (NSCLC). The present study aimed to assess the diagnostic and prognostic predictive values of four plasma miRNAs for NSCLC. A total of 12 candidate miRNAs were selected that have previously been reported to be aberrantly expressed in NSCLC, and their plasma levels in the training set were detected via reverse transcription-quantitative PCR analysis. The screened out miRNAs were further validated in the testing set. The area under the curve (AUC) of the receiver operating characteristic curve was constructed to evaluate diagnostic performance. Kaplan-Meier survival analysis was performed to assess the association between the plasma miRNA levels and disease-free survival (DFS) time. The results demonstrated that 4/12 plasma miRNAs (miR-210, miR-1290, miR-150 and miR-21-5p) were highly expressed in patients with NSCLC compared with their expression levels in patients with benign lung disease (BLD) and healthy controls in the training and testing sets, respectively. The AUC values of the four-miRNA panel were 0.96 and 0.93 in the training and testing sets, respectively, for distinguishing patients with NSCLC from healthy controls, which were similar to the AUC values for distinguishing patients with NSCLC from patients with BLD (0.96 and 0.94). The AUC values of the four-miRNA panel in patients with stage I NSCLC were comparable to that of patients with stage II-III NSCLC (0.942 and 0.965). Patients with high plasma levels of miR-210 and miR-150 had worse DFS than those with low plasma levels of these miRNAs. In addition, patients whose plasma levels of the four miRNAs decreased by >50% after surgery exhibited a good DFS. Taken together, the results of the present study suggest that these four miRNAs (miR-210, miR-1290, miR-150 and miR-21-5p) act as useful biomarkers for early diagnosis and prognosis of NSCLC.
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Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib and gefitinib, is a major clinical problem in the treatment of patients with non-small cell lung cancer (NSCLC). YM155 is a survivin small molecule inhibitor and has been demonstrated to induce cancer cell apoptosis and autophagy. EGFR-TKIs have been known to induce cancer cell autophagy. In this study, we showed that YM155 markedly enhanced the sensitivity of erlotinib to EGFR-TKI resistant NSCLC cell lines H1650 (EGFR exon 19 deletion and PTEN loss) and A549 (EGFR wild type and KRAS mutation) through inducing autophagy-dependent apoptosis and autophagic cell death. The effects of YM155 combined with erlotinib on apoptosis and autophagy inductions were more obvious than those of YM155 in combination with survivin knockdown by siRNA transfection, suggesting that YM155 induced autophagy and apoptosis in the NSCLC cells partially depend on survivin downregulation. Meanwhile, we found that the AKT/mTOR pathway is involved in modulation of survivin downregulation and autophagy induction caused by YM155. In addition, YM155 can induce DNA damage in H1650 and A549 cell lines. Moreover, combining erlotinib further augmented DNA damage by YM155, which were retarded by autophagy inhibitor 3MA, or knockdown of autophagy-related protein Beclin 1, revealing that YM155 induced DNA damage is autophagy-dependent. Similar results were also observed in vivo xenograft experiments. Therefore, combination of YM155 and erlotinib offers a promising therapeutic strategy in NSCLC with EGFR-TKI resistant phenotype.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/farmacologia , Imidazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Survivina/metabolismoRESUMO
The combination of platinum and gemcitabine is one of the standard regimens in the treatment of advanced lung squamous carcinoma (LSC). Resistance to gemcitabine is main barrier to the successful treatment of LSC. In this study, we showed that suppression of the Fanconi anemia (FA) pathway increased the sensitivity of two LSC cell lines SK-MES-1 and KLN205 to gemcitabine. Moreover, we found that the CHK1 pathway and the FA pathway are functionally compensatory in the repair of DNA damage in the LSC cell lines. Inactivation of one of the two pathways led to DNA damage, triggering compensatory activation of other pathway. Furthermore, we demonstrated that FANCD2 depletion combined with CHK1 inhibitor MK-8776 significantly potentiated the cytotoxicity of gemcitabine to the two LSC cell lines, compared to individual FANCD2 depletion or MK-8776 treatment. The enhanced effect of gemcitabine-chemosensitization was accompanied by loss of DNA repair function and accumulation of DNA single strand breaks and double strand breaks, in parallel with obvious increase of caspase-3 dependent apoptosis. Our results indicate that the enhancement effect of FANCD2 depletion combined with CHK1 inhibitor in sensitizing the LCS cells to gemcitabine supports the FA pathway and CHK1 as two therapeutic targets for improvement of anti-tumor regimens in treatment of LSC.
Assuntos
Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Desoxicitidina/análogos & derivados , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células A549 , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Quinase 1 do Ponto de Checagem/metabolismo , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Transdução de Sinais/genética , GencitabinaRESUMO
AIM: To summarize preoperative evaluation and outcome of corneal transplantation for limbal dermoids for ten years. METHODS: Eighty-five patients diagnosed with limbal dermoids and treated with corneal transplantation were analyzed retrospectively. All patients were further divided into two groups according to absence or presence of neovascularization surrounding the dermoids in the corneal stroma. Eighty-two eyes were treated with tumor excision combined with partial lamellar sclerokeratoplasty, and the other three eyes were performed by penetrating keratoplasty. The size and location of the tumor, the associated ocular and systemic anomalies, the depth of the corneal penetration of tumor tissues, the preoperative and postoperative best-corrected visual acuity (BCVA), graft survival and cosmetic outcome, and surgical complications were recorded respectively. RESULTS: The average age at surgery was 5.3y (range, 3mo-36y). The mean size of dermoids was 6.1±1.6 mm. The 43.5% of eyes (37/85) were present with hair at the surface of the dermoid and 72.9% of dermoids were located inferotemporal of the eye. Amplyopia was present in 34.1% of patients (29/85) and 9.4% of patients (8/85) had lipodermoids. Eighteen patients suffered from Goldenhar's syndrome with an accessory ear. The 75% of patients in group 1 had involvement of the corneal deep stroma down to Descemet's membrane without involving it, but 71.4% of patients had Descemet's membrane involvement in group 2. Preoperative BCVA ranged from counting fingers to 20/20. Postoperatively 81.1% had a BCVA of 20/800 or better. There was no significant difference between the post-surgical BCVA of the two groups (t=1.584, P>0.05). The grafts of 70.5% patients were present as 1+ opacity, 21.1% as 2+ opacity, 8.2% as 3+ opacity and none as 4+ opacity. Surgical complications included graft rejection, microperforation, prolonged reepithelialization, steroid glaucoma, interface neovascularization, and interface hemorrhage. CONCLUSION: The dermoids with neovascularization surrounding them in the corneal stroma invaded deeper tissues in the cornea than those with no neovascularization surrounding them in the corneal stroma. Therefore, surgeons should take care to avoid corneal perforation during the corneal transplantation operation. The majority of patients markedly improved their cosmetic appearance after surgery.
RESUMO
Cisplatin exert its anticancer effect by creating intrastrand and interstrand DNA cross-links which block DNA replication and is a major drug used to treat lung cancer. However, the main obstacle of the efficacy of treatment is drug resistance. Here, we show that expression of translesion synthesis (TLS) polymerase Q (POLQ) was significantly elevated by exposure of lung cancer cells A549/DR (a cisplatin-resistant A549 cell line) to cisplatin. POLQ expression correlated inversely with homologous recombination (HR) activity. Co-depletion of BRCA2 and POLQ by siRNA markedly increased sensitivity of A549/DR cells to cisplatin, which was accompanied with impairment of double strand breaks (DSBs) repair reflected by prominent cell cycle checkpoint response, increased chromosomal aberrations and persistent colocalization of p-ATM and 53BP1 foci induced by cisplatin. Thus, co-knockdown of POLQ and HR can efficiently synergize with cisplatin to inhibit A549/DR cell survival by inhibiting DNA DSBs repair. Similar results were observed in A549/DR cells co-depleted of BRCA2 and POLQ following BMN673 (a PARP inhibitor) treatment. Importantly, the sensitization effects to cisplatin and BMN673 in A549/DR cells by co-depleting BRCA2 and POLQ was stronger than those by co-depleting BRCA2 and other TLS factors including POLH, REV3, or REV1. Our results indicate that there is a synthetic lethal relationship between pol θ-mediated DNA repair and HR pathways. Pol θ may be considered as a novel target for lung cancer therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , DNA Polimerase Dirigida por DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Recombinação Homóloga/efeitos dos fármacos , Neoplasias Pulmonares/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Cisplatino/farmacologia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Recombinação Homóloga/genética , Humanos , DNA Polimerase tetaRESUMO
BACKGROUND: Cisplatin is one of the most commonly used chemotherapy agent for lung cancer. The therapeutic efficacy of cisplatin is limited by the development of resistance. In this study, we test the effect of RNA interference (RNAi) targeting Fanconi anemia (FA)/BRCA pathway upstream genes on the sensitivity of cisplatin-sensitive (A549 and SK-MES-1) and -resistant (A549/DDP) lung cancer cells to cisplatin. RESULT: Using small interfering RNA (siRNA), knockdown of FANCF, FANCL, or FANCD2 inhibited function of the FA/BRCA pathway in A549, A549/DDP and SK-MES-1 cells, and potentiated sensitivity of the three cells to cisplatin. The extent of proliferation inhibition induced by cisplatin after knockdown of FANCF and/or FANCL in A549/DDP cells was significantly greater than in A549 and SK-MES-1 cells, suggesting that depletion of FANCF and/or FANCL can reverse resistance of cisplatin-resistant lung cancer cells to cisplatin. Furthermore, knockdown of FANCL resulted in higher cisplatin sensitivity and dramatically elevated apoptosis rates compared with knockdown of FANCF in A549/DDP cells, indicating that FANCL play an important role in the repair of cisplatin-induced DNA damage. CONCLUSION: Knockdown of FANCF, FANCL, or FANCD2 by RNAi could synergize the effect of cisplatin on suppressing cell proliferation in cisplatin-resistant lung cancer cells through inhibition of FA/BRCA pathway.
Assuntos
Proteína BRCA1 , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteína do Grupo de Complementação D2 da Anemia de Fanconi , Proteína do Grupo de Complementação F da Anemia de Fanconi , Proteína do Grupo de Complementação L da Anemia de Fanconi , Neoplasias Pulmonares , Interferência de RNA , Transdução de Sinais , Proteína BRCA1/antagonistas & inibidores , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/antagonistas & inibidores , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação F da Anemia de Fanconi/antagonistas & inibidores , Proteína do Grupo de Complementação F da Anemia de Fanconi/genética , Proteína do Grupo de Complementação F da Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação L da Anemia de Fanconi/antagonistas & inibidores , Proteína do Grupo de Complementação L da Anemia de Fanconi/genética , Proteína do Grupo de Complementação L da Anemia de Fanconi/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Lymph node metastasis is a major prognostic factor in resected non-small cell lung cancer (NSCLC). However, 30-40 % rate of recurrence after performing complete resection in node-negative patients suggests that their nodal staging is suboptimal. We aimed to evaluate the molecular diagnosis and prognostic significance of lymph node micrometastasis in patients with node-negative NSCLC. Primary tumor samples from 62 patients with resected stage I-IIB NSCLC were screened for fragile histidine triad (FHIT) and CDKN2A mRNA deletion using reverse transcriptase polymerase chain reaction (RT-PCR). The molecular alternations were found in tumors of 49 patients. A total of 269 lymph nodes from these 49 NSCLC patients with FHIT or/and CDKN2A deletion tumors were examined. Fifteen positive-control nodes and ten negative-control nodes were also analyzed for FHIT and CDKN2A mRNA deletion. Thirty-nine (22 %) and 22 (18 %) lymph nodes from the 49 patients with FHIT and CDKN2A mRNA deletion in primary tumor had FHIT and CDKN2A mRNA deletion, respectively. The types of FHIT and CDKN2A mRNA deletion in lymph nodes were identical with those in their primary tumors. By combination of two markers, 16 patients (32.7 %) were found to have nodal micrometastasis. Survival analysis showed that patients with nodal micrometastasis had reduced disease-free survival (P = 0.001) and overall survival (P = 0.002) rates. Multivariate analysis demonstrated that nodal micrometastasis was an independent predictor for worse prognosis. Thus, the detection of lymph node micrometastasis by FHIT and CDKN2A mRNA deletion RT-PCR will be helpful to predict the recurrence and prognosis of patients with completely resected stage I-IIB NSCLC.
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Adenocarcinoma/patologia , Carcinoma Adenoescamoso/secundário , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/secundário , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Hidrolases Anidrido Ácido/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adulto , Idoso , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/mortalidade , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/mortalidade , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Micrometástase de Neoplasia , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de SobrevidaRESUMO
Survivin and livin are two members of the inhibitor of apoptosis gene family, which have been found to be expressed in many human cancer tissues. But their expression could not be detected in normal adult tissue. The aim of our study was to evaluate the diagnostic role of survivin and livin mRNA expression in the bronchial aspirates of patients with lung cancer. Seventy lung cancer patients and 26 benign lung disease patients participated in our study. The bronchial aspirates (bronchial wash or bronchoalveolar lavage fluids) obtained during bronchoscopy. Survivin and livin mRNA were determined by reverse transcriptase-polymerase chain reaction. Receiver operating characteristic (ROC) curve was used to analyze diagnostic performance of the two markers. Survivin and livin mRNA levels in patients with lung cancer were significantly higher than in those with benign lung disease (p < 0.001 and p = 0.001, respectively). In lung cancer patients, specimens taken from cancerous bronchi had significantly higher levels of survivin and livin mRNA than specimens from the mirror side bronchi in the same patients (p < 0.001 and p = 0.001, respectively). The best cutoff values of survivin and livin were selected according to ROC curves. The survivin mRNA expression in bronchial aspirates had sensitivity and specificity of 83 and 96% for diagnosis of lung cancer. Livin mRNA detection in bronchial aspirates showed 63% sensitivity and 92% specificity. Our findings suggest that survivin and livin mRNA detection in bronchial aspirates may be valuable diagnostic marker for the early diagnosis of lung cancer.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores Tumorais/genética , Proteínas Inibidoras de Apoptose/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , RNA Mensageiro/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Brônquios/metabolismo , Líquido da Lavagem Broncoalveolar/química , Broncoscopia/métodos , Feminino , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , RNA Mensageiro/metabolismo , SurvivinaRESUMO
AIM: To evaluate the efficacy of current chemoradiotherapy on improvement of survival in patients with superior sulcus non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed the data of 39 patients with superior sulcus NSCLC treated with induction therapy followed surgery. The patients were divided into two groups according to the induction approach: the induction radiotherapy (RT) group (1993-1999), and the induction chemoradiotherapy (CT/RT) group (since 1999). RESULTS: The rate of complete resection was 65 percent in the RT group (n = 17) compared with 91 percent in the CT/RT group (n = 22, P = 0.024). Complete pathological responses from induction therapy were 12 percent in the RT group and 45 percent in the CT/RT group (P = 0.032). Overall survival (OS) was significantly longer in patients who received CT/RT than that in those who received RT, with 2- and 5-year survival rates of 77.3 percent and 36.4 percent versus 41.2 percent and 11.8 percent, respectively (P = 0.007). CT/RT also associated with a markedly longer tumor-free survival (TFS), with a median TFS of 40 and 17 months, respectively (P = 0.007). Patients achieved complete resection or complete pathological response had a significantly better survival than those with incomplete resection or pathological partial responses and no change (P < 0.0005 and P = 0.001, respectively). CONCLUSION: Our results indicate that CT/RT followed by surgery can significantly improve OS and TFS, and may be considered as an optimal option in treatment of patients with superior sulcus NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Síndrome de Pancoast/terapia , Adulto , Idoso , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVE: Survivin and X-linked inhibitor of apoptosis protein (XIAP) in vitro mediate cancer cell survival and chemoresistance. Second mitochondria-derived activator of caspases (Smac), an antagonist of XIAP, has been shown in vitro to increase chemosensitivity. This study examined the prognostic value of survivin, XIAP and Smac in advanced non-small-cell lung cancer (NSCLC) patients treated with cisplatin-containing chemotherapy. METHODS: Semi-quantitative RT-PCR was used to measure survivin, XIAP and Smac mRNA expression in transbronchial biopsy tumour specimens from 72 patients with advanced NSCLC before commencing chemotherapy. Outcome measures were response to chemotherapy, progression-free survival (PFS) and overall survival (OS). RESULTS: Low expression of survivin was associated with good response to chemotherapy (P = 0.028). No association was found between XIAP and Smac expression levels and response to chemotherapy (P = 0.224 and P = 0.088, respectively). Patients with low survivin expression or high Smac expression had significantly longer PFS (P = 0.012 and P = 0.029, respectively) and OS (P = 0.007 and P = 0.031, respectively) compared with patients with high expression of survivin or low expression of Smac. XIAP expression was not correlated with PFS or OS. Additionally, PFS and OS in patients with performance status of 0 or 1 and stage IIIB were significantly longer than PFS and OS in patients with performance status (PS) of 2 and stage IV disease. Multivariate Cox regression analyses demonstrated that survivin and clinical stage were independent predictors for PFS and OS. Smac was an independent prognostic factor for OS, but not for PFS. CONCLUSIONS: Our findings suggest that the expression levels of survivin and Smac, but not XIAP, predict the survival of patients with advanced NSCLC treated with chemotherapy.
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Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Adulto , Idoso , Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose , Biópsia , Brônquios/metabolismo , Brônquios/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , RNA Mensageiro/metabolismo , Análise de Regressão , Estudos Retrospectivos , Survivina , Resultado do TratamentoRESUMO
OBJECTIVE: Survivin and livin, which are members of the inhibitor of apoptosis protein family, regulate both programmed cell death and proliferation. Second mitochondria-derived activator of caspase is thought to regulate apoptosis by antagonizing inhibitor of apoptosis protein. These gene expressions are regarded as prognostic markers in some malignancies. However, result in previous studies of the association of these gene expressions with prognosis of patients with non-small cell lung cancer remains contradictory. METHODS: Survivin, livin and second mitochondria-derived activator of caspase mRNA was detected by semi-quantitative reverse transcriptase-polymerase chain reaction in surgical resected tumor specimen from 66 non-small cell lung patients who received adjuvant platinum-based chemotherapy. RESULTS: Results showed that patients with survivin high expression had significantly shorter tumor-free survival (P = 0.012) and overall survival (P = 0.007) than those with survivin low expression. There was a significant association of second mitochondria-derived activator of caspase high expression in non-small cell lung cancer tissue with longer tumor-free survival (P = 0.021) and overall survival (P = 0.0013). However, livin mRNA expression level had no impact on the tumor-free survival and overall survival of the patients. In multivariate analyses, survivin mRNA high expression (P = 0.033 and P = 0.024) and advanced pathologic stage (P = 0.009 and P = 0.008) were the factors which independently predicted a worse tumor-free survival and overall survival. CONCLUSIONS: Our data suggest that assessment of survivin and second mitochondria-derived activator of caspase mRNA expression may be useful for predicting survival in non-small cell lung cancer patients receiving platinum-based chemotherapy after surgical resection and can provide valuable information for deciding better therapy strategy.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas Mitocondriais/biossíntese , Adulto , Idoso , Proteínas Reguladoras de Apoptose , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimioterapia Adjuvante , Feminino , Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Pneumonectomia , Prognóstico , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SurvivinaRESUMO
The purposes of this study were to evaluate the treatment outcome of patients with small cell lung cancer (SCLC), focusing on the prognostic factors for response to therapy and overall survival. A retrospective analysis was performed on 116 consecutive patients with SCLC diagnosed from January 1997 to December 2005. Collected data included demographic information, pretreatment clinical assessment, treatment regimen, and outcome information. Prognostic factors were analyzed by log-rank test and Cox regression model. Results showed that performance status (PS) 0-1, limited disease, normal serum carcinoembryonic antigen (CEA), and vascular endothelial growth factor (VEGF) level were associated with improved response rate. The univariate analysis showed that sex, disease extent, PS, serum CEA, and VEGF level significantly influenced overall survival. In multivariate analysis, disease extent, PS, serum CEA, and VEGF level were identified as independent prognostic factors. In addition, prophylactic cranial irradiation (PCI) and number of metastatic sites were independent prognostic factors in limited disease and extensive disease, respectively. We concluded that disease extent, PS, serum CEA, and VEGF level are strong predictors of both response and survival. Female sex was a favorable prognostic factor for survival. Moreover, the prognostic factors for limited disease were good PS, normal serum CEA and VEGF level, and PCI, the prognostic factors for extensive disease were good PS, one metastatic site, normal serum CEA, and VEGF level. The identification of prognostic factors may be useful for the better evaluation of treatment outcome in clinical trials and the use of a targeted and specific treatment.
Assuntos
Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Antígeno Carcinoembrionário/análise , Antígeno Carcinoembrionário/sangue , Terapia Combinada , Irradiação Craniana , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores Sexuais , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/terapia , Taxa de Sobrevida , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
The title compound, C(14)H(11)N(3)O(4), was prepared by the reaction of 4-nitro-benzohydrazide with 4-hy-droxy-benz-alde-hyde. The whole mol-ecule of the compound is approximately planar, with a mean deviation from the least-squares plane through all the non-H atoms of 0.050â (2)â Å; the dihedral angle between the two benzene rings is 2.0â (2)°. In the crystal, the benzohydrazide mol-ecules are linked through inter-molecular O-Hâ¯O and N-Hâ¯O hydrogen bonds, forming layers in the bc plane.
RESUMO
The title mol-ecule, C(14)H(11)N(3)O(4), is approximately planar, with an inter-planar angle between the two benzene rings of 5.8â (2)°. In the crystal, four mol-ecules are linked by an R(4) (4)(12) motif with pairs of strong O-Hâ¯O and N-Hâ¯O hydrogen bonds. The motif is situated about the crystallographic centres of symmetry and it is composed of two pairs of parallel mol-ecules. This quadruplet of mol-ecules is further extended by symmetry-equivalent hydrogen bonds to form layers parallel to the (10) plane. In addition to the hydrogen bonds, there is also a weak π-π inter-action between the benzene rings.
RESUMO
The title compound, C(14)H(9)Cl(2)N(3)O(3), was prepared by the reaction of 3-nitro-benzohydrazide with 2,4-dichloro-benzalde-hyde. The mol-ecule adopts an E configuration about the C=N bond. The dihedral angle between the two benzene rings is 4.6â (2)°. In the crystal, the hydrazone mol-ecules are linked through inter-molecular N-Hâ¯O hydrogen bonds, forming chains along the c axis.
RESUMO
The title compound, C(14)H(11)N(3)O(4), was prepared by the reaction of 3-nitro-benzohydrazide with 3-hy-droxy-benzalde-hyde. The mol-ecule adopts an E configuration about the C=N bond. The dihedral angle between the two benzene rings is 32.3â (2)°. In the crystal, the mol-ecules are linked through inter-molecular N-Hâ¯O, O-Hâ¯N, and O-Hâ¯O hydrogen bonds, forming chains in the a-axis direction.
RESUMO
BACKGROUND: Prognosis of stage IIIA N2 non-small cell lung cancer (NSCLC) remains poor despite the changes in therapeutic strategies. OBJECTIVES: To assess long term results of neo adjuvant therapy followed by surgery for patients with stage IIIA N2 NSCLC and to analyze factors influencing survival. MATERIALS AND METHODS: The methods adopted include: Retrospective review of medical records of 91 patients with stage IIIA N2 NSCLC, who received neo adjuvant therapy followed by surgery; collection of information on demographic information, staging procedure, preoperative therapy, clinical response, type of resection, pathologic response of tumor, status of lymph nodes and adjuvant chemotherapy; survival analysis by Kaplan-Meier and calculation of prognostic factors using log-rank and Cox regression model. RESULTS: All patients received a platinum-based chemotherapy and 23 (29.1%) had an associated radiotherapy. Eighty four patients underwent thoracotomy. Median survival was 26 months (95%CI, 22.6-30.8 months) with three and five year survival rates of 31.6 and 20.9%, respectively. Prognostic factors for survival on univariate analysis was clinical response (P = 0.032), complete resection (P = 0.002), pathologic tumor response ( P < 0.001), and lymph nodal down staging (P = 0.001). Multivariate analyses identified complete resection, pathologic tumor response and lymph nodal down staging as independent prognostic factors. CONCLUSION: Survival of patients with stage IIIA N2 NSCLC who received neo adjuvant therapy is significantly influenced by clinical response, complete resection, pathologic tumor response, and lymph nodal down staging. These results can be helpful in guiding standard clinical practice and evaluating the outcome of neo adjuvant therapy followed by surgery in patients with stage IIIA N2 NSCLC.