RESUMEN

Objective: This study aimed to explore the efficacy of transarterial chemoembolization (TACE) combined with microwave ablation (MWA) adjuvant to lenvatinib and anti-PD-1 antibodies for patients with hepatocellular carcinoma (HCC). Methods: A retrospective analysis of 67 patients with HCC treated at our hospital between October 2018 and May 2022 was conducted. All patients underwent a combination of TACE and MWA. Among them, 29 received postoperative treatment with molecular-targeted agents, like lenvatinib, along with anti-PD-1 antibodies such as sindilizumab, karelizumab, or tirilizumab. The remaining 38 patients did not receive postoperative systemic therapies, like targeted or immunotherapy. The survival and prognosis of all patients were analyzed. Results: Nine patients in the observation group and 29 patients in the control group experienced recurrence, and the median progression-free survival 1 (PFS1) was not reached 'Not Applicable'(NA) and 17.05 months (P=0.035), respectively. Failure to combine adjuvant therapy was identified as an independent risk factor for tumor recurrence, and the observation group had a 0.245 times lower risk of recurrence compared to that in the control group (P=0.005). Multivariable Cox regression analysis confirmed that the maximum tumor size, and tumor number were risk factors for tumor recurrence. Patients with a large maximum tumor size had a 1.519 times higher risk of recurrence compared to those with a small maximum tumor size (P=0.006), and patients with a large number of tumors had a 5.978 times higher risk of recurrence compared to those with a small number of tumors (P=0.02). The median PFS2 of the two groups was 11.795 and 21.257 months, respectively, though not statistically significant (P=0.955). However, there was a disparity in the percentage of BCLC stages associated with recurrence between the two groups. In the observation group approximately 22.22% of patients progressed to stage C, while in the control group, this proportion was 34.48%. The observation group exhibited a lower risk of distant metastasis compared to the control group. Conclusion: Adjuvant treatment of HCC following TACE combined with MWA improved PFS and achieved better clinical outcomes compared to that with TACE combined with MWA alone.

Asunto(s)

Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/terapia , Estudios Retrospectivos , Microondas/uso terapéutico , Resultado del Tratamiento , Quimioembolización Terapéutica/efectos adversos

RESUMEN

Exosomes are progressively being detected as an indicator for the diagnosis and prognosis of cancer in clinical settings. Many clinical trials have confirmed the impact of exosomes on tumor growth, particularly in anti-tumor immunity and immunosuppression of exosomes. Therefore, we developed a risk score based on genes found in glioblastoma-derived exosomes. In this study, we used the TCGA dataset as the training queue and GSE13041, GSE43378, GSE4412, and CGGA datasets as the external validation queue. Based on machine algorithms and bioinformatics methods, an exosome-generalized risk score was established. We found that the risk score could independently predict the prognosis of patients with glioma, and there were significant differences in the outcomes of patients in the high- and low-risk groups. Univariate and multivariate analyses showed that risk score is a valid predictive biomarker for gliomas. Two immunotherapy datasets, IMvigor210 and GSE78220, were obtained from previous studies. A high-risk score showed a significant association with multiple immunomodulators that could act on cancer immune evasion. The exosome-related risk score could predict the effectiveness of anti-PD-1 immunotherapy. Moreover, we compared the sensitivity of patients with high- and low-risk scores to various anti-cancer drugs and found that patients with high-risk scores had better responses to a variety of anti-cancer drugs. The risk-scoring model established in this study provides a useful tool to predict the total survival time of patients with glioma and guide immunotherapy.

Asunto(s)

Exosomas , Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Pronóstico , Exosomas/genética , Biomarcadores

RESUMEN

PURPOSE: The aim of the study is to assess the clinical value of the combined computed tomography (CT)/ultrasound (US) guidance in microwave ablation (MWA) for hepatocellular carcinoma (HCC). METHODS: From July 16, 2016, to June 20, 2021, medical records of 150 HCC patients treated with MWA were retrospectively analyzed. Ninety-two patients with 115 liver tumors underwent MWA under combined CT/US guidance, and 58 patients with 73 liver tumors received MWA under CT guidance alone. The clinical efficacy of combined CT/US-guided MWA was analyzed. We compared the complications, procedure time, and CT scan times between the 2 groups. RESULTS: The total complete ablation rate and complete ablation rate of high-risk location tumors were significantly higher in the group treated with combined CT/US guidance ( P = 0.0471 and P = 0.0347, respectively), the imaging guidance modality (odds ratio, 0.303; 95% confidence interval [CI], 0.095-0.970; P = 0.044) was an independent factor for ablation efficacy. These 2 groups also had significant differences in the procedure time ( P = 0.0171), the incidence rate of pneumothorax ( P = 0.0209), abdominal pain ( P = 0.0196), nausea or vomiting ( P = 0.0026), and intraoperative CT scan times ( P < 0.001). The overall complication rates ( P = 0.4023) and recurrence rates ( P = 0.5063) between the 2 groups were not statistically significant. However, CT/US group has a better short-term progressive free survival (log-rank P = 0.103, Breslow P = 0.030). In multivariate analysis, guidance modality (hazard ratio, 0.586; 95% CI, 0.368-0.934; P = 0.025) and Barcelona Clinic Liver Cancer stage (hazard ratio, 2.933; 95% CI, 1.678-5.127; P < 0.001) were risk factor for progressive free survival. CONCLUSIONS: Percutaneous MWA under the combined CT/US guidance for HCC can improve clinical benefits.

Asunto(s)

Carcinoma Hepatocelular , Ablación por Catéter , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Microondas/uso terapéutico , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Ablación por Catéter/métodos

RESUMEN

Breast cancer is the most common malignancy and the leading cause of cancer-related deaths in women. Recent studies have investigated the prognostic value of the tumor microenvironment (TME)-related genes in breast cancer. The purpose of this research is to identify the immune-associated prognostic signature for breast cancer evaluate the probability of their prognostic value and compare the current staging system. In this study, we comprehensively evaluated the infiltration patterns of TME in 1,077 breast cancer patients downloaded from TCGA by applying the ssGSEA method to the transcriptome of these patients. Thus, generated two groups of immune cell infiltration. Based on two groups of low infiltration and high infiltration immune cell groups, 983 common differentially expressed genes were found using the limma algorithm. In addition, studying potential mechanisms, the GSEA method was used to indicate some pathways with remarkable enrichment in two clusters of immune cell infiltration. Finally, the seven immune-associated hub genes with survival as prognostic signatures were identified by using univariate Cox, survival, and LASSO analyses and constructed a TME score. The prognostic value of the TME score was self-validated in the TCGA cohort and further validated in an external independent set from METABRIC and GEO database by time-dependent survival receiver operation. Univariate and multivariate analyses of clinicopathological characteristics indicated that the TME score was an independent prognostic factor. In conclusion, the proposed TME score model should be considered as a prognostic factor, similar to the current TNM stage, and the seven immune-related genes can be a valuable potential biomarker for breast cancer.

RESUMEN

When the adenoviral protein E1B55K binds death domain-associated protein (Daxx), the proteasome-dependent degradation of Daxx is initiated, and adenoviral replication is effectively maintained. Here, we show that the cellular levels of Daxx differ between human and mouse cancer cell lines. Specifically, we observed higher cellular Daxx levels and the diminished replication of oncolytic adenovirus in mouse cancer cell lines, suggesting that cellular Daxx levels limit the replication of oncolytic adenoviruses that lack E1B55K in murine cells. Indeed, the replication of oncolytic adenoviruses that lack E1B55K was significantly increased following infection with oncolytic adenovirus expressing Daxx-specific shRNA. Cellular Daxx levels were decreased in mouse cells expressing heat shock protein 25 (HSP25; homolog of human HSP27) following heat shock or stable transfection with HSP25-bearing plasmids. Furthermore, Daxx expression in murine cell lines was primarily regulated at the transcriptional level via HSP25-mediated inhibition of the nuclear translocation of the signal transducer and activator of transcription 3 (stat3) protein, which typically upregulates Daxx transcription. Conversely, human HSP27 enhanced stat3 activity to increase Daxx transcription. Interestingly, human Daxx, but not mouse Daxx, was degraded as normal by ubiquitin-dependent lysosomal degradation; however, HSP27 downregulation induced the ubiquitin-independent proteasomal degradation of Daxx.

Asunto(s)

Proteínas Co-Represoras/genética , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Neoplasias/genética , Adenoviridae/genética , Animales , Línea Celular Tumoral , Humanos , Ratones , Neoplasias/terapia , Neoplasias/virología , Virus Oncolíticos/genética , Factor de Transcripción STAT3/genética , Ubiquitina/genética , Replicación Viral/genética

RESUMEN

Transforming growth factor (TGF)-ß signaling is increasingly recognized as a key driver in cancer. In progressive cancer tissues, TGF-ß promotes tumor formation, and its increased expression often correlates with cancer malignancy. In this study, we utilized adenoviruses expressing short hairpin RNAs against TGF-ß1 and TGF-ß2 to investigate the role of TGF-ß downregulation in cancer cell death. We found that the downregulation of TGF-ß increased the phosphorylation of several SAPKs, such as p38 and JNK. Moreover, reactive oxygen species (ROS) production was also increased by TGF-ß downregulation, which triggered Akt inactivation and NOX4 increase-derived ROS in a cancer cell-type-specific manner. We also revealed the possibility of substantial gene fluctuation in response to TGF-ß downregulation related to SAPKs. The expression levels of Trx and GSTM1, which encode inhibitory proteins that bind to ASK1, were reduced, likely a result of the altered translocation of Smad complex proteins rather than from ROS production. Instead, both ROS and ROS-mediated ER stress were responsible for the decrease in interactions between ASK1 and Trx or GSTM1. Through these pathways, ASK1 was activated and induced cytotoxic tumor cell death via p38/JNK activation and (or) induction of ER stress.

Asunto(s)

Estrés del Retículo Endoplásmico/inmunología , MAP Quinasa Quinasa 4/metabolismo , Neoplasias/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Células A549 , Muerte Celular , Regulación hacia Abajo , Humanos , Péptidos y Proteínas de Señalización Intracelular , MAP Quinasa Quinasa Quinasa 5/metabolismo , Proteínas de la Membrana/metabolismo , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , Neoplasias/patología , Proteína Oncogénica v-akt/genética , Proteína Oncogénica v-akt/metabolismo , Fosforilación , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/genética

RESUMEN

PURPOSE: Sorafenib, a multikinase inhibitor, is the standard therapy for patients with advanced-stage hepatocellular carcinoma (HCC). However, resistance develops to the treatment, therefore, we tried to unravel the underlying mechanism in the resistance of HCC cells to sorafenib via the development of more effective therapeutic strategies. MATERIALS AND METHODS: Various liver cancer cell lines were treated with either sorafenib only or with sorafenib after infection of adenovirus expressing short hairpin RNA (shRNA) against transforming growth factor-ß (TGF-ß) and p38 activity was examined using western blotting. RESULTS: p38 MAP kinase activity was inhibited by low concentrations of sorafenib, which could potentially lead to sorafenib resistance in HCC cell lines. Subsequently, we used constitutive form of MKK3/6 (MKK3/6E) to confirm that massive cell death was induced by the activation of p38, and demonstrated the ability to activate p38 without any stimulation. In addition, sorafenib resistance was reduced by the activation of p38. Subsequently, we confirmed that TGF-ß shRNA effectively recovered the phosphorylation of p38 inhibited by sorafenib, and increased the sensitivity of HCC cells to sorafenib, thereby inducing cell death and overcoming the resistance of HCC cells to sorafenib. CONCLUSION: Our study provides a new therapeutic strategy for HCC that overcomes the resistance of HCC to sorafenib by down-regulation of TGF-ß.

Asunto(s)

Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Hepáticas/patología , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacología , Factor de Crecimiento Transformador beta/metabolismo , Adenoviridae/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Niacinamida/farmacología , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Fosforilación/efectos de los fármacos , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Sorafenib , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo

RESUMEN

In this study, we demonstrated that survivin downregulation with TRAIL expression greatly enhanced the cytotoxic death of pancreatic cancer cells after gemcitabine treatment. Using real-time RT-PCR, we analyzed five survivin shRNAs to identify the best target sequence for suppression of human survivin, with the goal of treating gemcitabine-resistant pancreatic cancer cells. Survivin shRNA 5, corresponding to target 5, showed the greatest reduction in survivin mRNA levels. Furthermore, combined treatment with survivin shRNA-expressing adenovirus with gemcitabine plus TRAIL decreased uncleaved PARP and increased consequent PARP cleavage, which was correlated with the greatest levels of survivin downregulation and cell death. These results indicate that survivin functions as a common mediator of gemcitabine- and TRAIL-induced cell death. Using a nude mouse model implanted with MiaPaCa-2 pancreatic cancer cells, we observed tumor regression induced by an oncolytic adenovirus expressing survivin shRNA and TRAIL plus gemcitabine. Together, our findings provide a strong rationale for treating pancreatic cancer patients with both gemcitabine and oncolytic adenovirus armed with survivin shRNA and TRAIL.

Asunto(s)

Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/genética , Proteínas Inhibidoras de la Apoptosis/genética , Viroterapia Oncolítica/métodos , Virus Oncolíticos , Neoplasias Pancreáticas/terapia , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Adenoviridae , Animales , Apoptosis , Línea Celular Tumoral , Terapia Combinada , Desoxicitidina/uso terapéutico , Regulación hacia Abajo , Femenino , Células HEK293 , Humanos , Ratones , Ratones Desnudos , Interferencia de ARN , ARN Interferente Pequeño/genética , Survivin , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina

RESUMEN

Gemcitabine has been used most commonly as an anticancer drug to treat advanced pancreatic cancer patients. However, intrinsic or acquired resistance of pancreatic cancer to gemcitabine was also developed, which leads to very low five-year survival rates. Here, we investigated whether cellular levels of HSP27 phosphorylation act as a determinant of cellular fate with gemcitabine. In addition we have demonstrated whether HSP27 downregulation effectively could overcome the acquisition of gemcitabine resistance by using transcriptomic analysis. We observed that gemcitabine induced p38/HSP27 phosphorylation and caused acquired resistance. After acquisition of gemcitabine resistance, cancer cells showed higher activity of NF-κB. NF-κB activity, as well as colony formation in gemcitabine-resistant pancreatic cancer cells, was significantly decreased by HSP27 downregulation and subsequent TRAIL treatment, showing that HSP27 was a common network mediator of gemcitabine/TRAIL-induced cell death. After transcriptomic analysis, gene fluctuation after HSP27 downregulation was very similar to that of pancreatic cancer cells susceptible to gemcitabine, and then in opposite position to that of acquired gemcitabine resistance, which makes it possible to downregulate HSP27 to overcome the acquired gemcitabine resistance to function as an overall survival network inhibitor. Most importantly, we demonstrated that the ratio of phosphorylated HSP27 to nonphosphorylated HSP27 rather than the cellular level of HSP27 itself acts biphasically as a determinant of cellular fate in gemcitabine-resistant pancreatic cancer cells.

Asunto(s)

Antimetabolitos Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Proteínas de Choque Térmico HSP27/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Antimetabolitos Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Regulación hacia Abajo , Perfilación de la Expresión Génica , Proteínas de Choque Térmico HSP27/análisis , Proteínas de Choque Térmico HSP27/genética , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , FN-kappa B/metabolismo , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Fosforilación , Gemcitabina

RESUMEN

Although gene therapy was regarded as a promising approach for glioma treatment, its therapeutic efficacy was often disappointing because of the lack of efficient drug delivery systems. Mesenchymal stem cells(MSCs) have been reported to have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. Therefore, in this study, we attempted to treat glioma by using MSCs as a vehicle for delivering replication-competent adenovirus. We firstly compared the infectivity of type 3, type 5, and type 35 fiber-modified adenoviruses in MSCs. We also determined suitable adenovirus titer in vitro and then used this titer to analyze the ability of MSCs to deliver replication-competent adenovirus into glioma in vivo. Our results indicated that type 35 fiber-modified adenovirus showed higher infectivity than did naked type 3 or type 5 fiber-modified adenovirus. MSCs carrying replication-competent adenovirus significantly inhibited tumor growth in vivo compared with other control groups. In conclusion, MSCs are an effective vehicle that can successfully transport replication-competent adenovirus into glioma, making it a potential therapeutic strategy for treating malignant glioma.

Asunto(s)

Adenoviridae , Neoplasias Encefálicas/terapia , Glioma/terapia , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Viroterapia Oncolítica , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Vectores Genéticos , Glioma/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Distribución Aleatoria , Replicación Viral , Ensayos Antitumor por Modelo de Xenoinjerto