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1.
Heliyon ; 10(10): e31071, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38803891

RESUMEN

Objective: The Obturator Functioning Scale (OFS) is a scale without formal measures of validity in any language. This study aimed to translate and adapt the OFS from English to Chinese and check its reliability and validity in Chinese-speaking patients with obturator prostheses after cancer-related maxillectomy. Methods: The 15-item Chinese preversion of the OFS was completed by 133 patients in three tertiary stomatological hospitals. Of these, 41 completed it again one week after the first measurement. The patients also completed the Chinese version of the University of Washington quality of life scale (UW-QOL, Version 4). Results: Item 12 ("upper lip feels numb") was deleted to achieve a better statistical fit. The 14-item Chinese version of the OFS (OFS-Ch) demonstrated high internal consistency (Cronbach's alpha = 0.908). The test-retest reliability coefficients for most items exceeded 0.90, indicating substantial reproducibility. Confirmatory factor analysis found that the scale consisted of three correlated factors: 1) eating (four items), 2) speech (five items), and 3) other problems (five items). This explained 70.2 % of the total variance using exploratory factor analysis. The scale was significantly convergent and discriminant and could validly discriminate between patients with Brown I and IId maxillary defects. Conclusions: Our results showed that the OFS-Ch scale is a valid tool for evaluating oral dysfunction and satisfaction with appearance for patients with the obturator prosthesis and identifying those at risk of poor obturator function in clinical settings.

2.
Chem Biol Drug Des ; 103(4): e14519, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38570708

RESUMEN

Kaempferol (KPR), a flavonoid compound found in various plants and foods, has garnered attention for its anti-inflammatory, antioxidant, and anticancer properties. In preliminary studies, KPR can modulate several signaling pathways involved in inflammation, making it a candidate for treating cholecystitis. This study aimed to explore the effects and mechanisms of KPR on lipopolysaccharide (LPS)-induced human gallbladder epithelial cells (HGBECs). To assess the impact of KPR on HGBECs, the HGBECs were divided into control, KPR, LPS, LPS + KPR, and LPS + UDCA groups. Cell viability and cytotoxicity were evaluated by MTT assay and lactate dehydrogenase (LDH) assay, respectively, and concentrations of KPR (10-200 µM) were tested. LPS-induced inflammatory responses in HGBECs were to create an in vitro model of cholecystitis. The key inflammatory markers (IL-1ß, IL-6, and TNF-α) levels were quantified using ELISA, The modulation of the MAPK/NF-κB signaling pathway was measured by western blot using specific antibodies against pathway components (p-IκBα, IκBα, p-p65, p65, p-JNK, JNK, p-ERK, ERK, p-p38, and p38). The cell viability and LDH levels in HGBECs were not significantly affected by 50 µM KPR, thus it was selected as the optimal KPR intervention concentration. KPR increased the viability of LPS-induced HGBECs. Additionally, KPR inhibited the inflammatory factors level (IL-1ß, IL-6, and TNF-α) and protein expression (iNOS and COX-2) in LPS-induced HGBECs. Furthermore, KPR reversed LPS-induced elevation of p-IκBα/IκBα, p-p65/p65, p-JNK/JNK, p-ERK/ERK, and p-p38/p38 ratios. KPR attenuates the LPS-induced inflammatory response in HGBECs, possibly by inhibiting MAPK/NF-κB signaling.


Asunto(s)
Colecistitis , FN-kappa B , Humanos , FN-kappa B/metabolismo , Lipopolisacáridos/toxicidad , Inhibidor NF-kappaB alfa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Quempferoles/farmacología , Transducción de Señal , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Células Epiteliales/metabolismo , Sistema de Señalización de MAP Quinasas
3.
Br J Radiol ; 92(1104): 20190480, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31596123

RESUMEN

OBJECTIVE: To evaluate the diagnostic accuracy of multiparametric MRI (mpMRI) for detecting extracapsular extension (ECE) in patients with prostate cancer (PCa). METHODS AND MATERIALS: We searched MEDLINE, PubMed, Embase and the Cochrane library up to December 2018. We included studies that used mpMRI to differentiate ECE from organ-confined PCa with a combination of T2 weighted imaging (T2WI), diffusion-weighted imaging, and dynamic contrast-enhanced MRI. All studies included had pathological diagnosis with radical prostatectomy. Two reviewers independently assessed the methodological quality of included studies by using Quality Assessment of Diagnostic Accuracy Studies 2 tool. We calculated pooled sensitivity, specificity, positive and negative predictive values, diagnostic odds ratios and receiver operating characteristic curve for mpMRI from 2 × 2 tables. RESULTS: A total of 17 studies that comprised 3374 participants were included. The pooled data showed a sensitivity of 0.55 (95% confidence interval 0.43, 0.66]) and specificity of 0.87 (95% confidence interval 0.82, 0.91) for extracapsular extension detection in PCa. CONCLUSION: First, our meta-analysis shows moderate sensitivity and high specificity for mpMRI to differentiate ECE from organ-confined prostate cancer before surgery. Second, our meta-analysis shows that mpMRI had no significant differences in performance compared with the former meta-analysis with use of T2WI alone or with additional functional MRI. ADVANCES IN KNOWLEDGE: It is the first meta-analysis to evaluate the accuracy of mpMRI in combination of TWI, diffusion-weightedimaging and dynamiccontrast-enhanced-MRI for extracapsular extension detection.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Próstata/diagnóstico por imagen , Neoplasias de la Próstata/diagnóstico por imagen , Intervalos de Confianza , Medios de Contraste , Imagen de Difusión por Resonancia Magnética/métodos , Humanos , Masculino , Cuidados Preoperatorios , Próstata/patología , Próstata/cirugía , Prostatectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Curva ROC , Sensibilidad y Especificidad
4.
Neurosci Lett ; 708: 134345, 2019 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-31229623

RESUMEN

Although brain-derived neurotrophic factor (BDNF) induces the differentiation of induced pluripotent stem cells (iPSCs) into neural stem cells (NSCs), its exact mechanism remains unelucidated. Wnt/ß-catenin and ERK5 are two important signalling pathways of the Wnt and MAPK signalling cascades and are speculated to be closely related to the differentiation of cells. In this study, we reported the role of the Wnt/ß-catenin and ERK5 signalling pathways on the BDNF-induced differentiation of iPSCs into NSCs. We examined the expression of ß-catenin and p-ERK5 using small interfering RNA (siRNA)-induced silencing of ß-catenin and ERK genes. We found that BDNF significantly improved the efficiency of iPSC differentiation and that the expression of ß-catenin and p-ERK5 in the BDNF culture medium was significantly upregulated. Furthermore, we found that the expression of the ß-catenin component was downregulated by siRNA-ß-catenin, and the expression of the p-ERK5 component was downregulated by siRNA-ERK5. Flow cytometry showed that the differentiation rate of iPSCs was also significantly decreased by RNA interference. The results suggested that the Wnt/ß-catenin and ERK5 signalling pathways are activated in the process of BDNF-induced iPSC differentiation. Interestingly, our study showed that siRNA-ERK5 not only inhibits the activity of the ERK5 signalling pathway but also partially controls the activity of the Wnt/ß-catenin signalling pathway. The results suggested that the Wnt/ß-catenin and ERK5 signalling pathways are not independently involved in the process of BDNF-induced iPSC differentiation. Our study showed that BDNF promotes the differentiation of iPSCs into NSCs by activating the Wnt/ß-catenin and ERK5 signalling pathways, and an interconnected relationship may exist between the Wnt/ß-catenin and ERK5 signalling pathways.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Madre Pluripotentes Inducidas/citología , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Células-Madre Neurales/citología , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/farmacología , Diferenciación Celular , Células Cultivadas , Ratones Endogámicos C57BL , Proteína Quinasa 7 Activada por Mitógenos/genética , ARN Interferente Pequeño/genética , Transducción de Señal , beta Catenina/genética
5.
Vaccine ; 37(31): 4382-4391, 2019 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-31202521

RESUMEN

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8+ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα+ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.


Asunto(s)
Neoplasias de la Mama/etiología , Neoplasias de la Mama/patología , Gelatinasas/genética , Gelatinasas/inmunología , Expresión Génica , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Serina Endopeptidasas/genética , Serina Endopeptidasas/inmunología , Microambiente Tumoral , Vacunas de ADN/genética , Vacunas de ADN/inmunología , Animales , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Endopeptidasas , Femenino , Humanos , Inmunogenicidad Vacunal , Ratones , Plásmidos/genética , Resultado del Tratamiento , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Vacunas de ADN/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
6.
J Am Coll Radiol ; 16(4 Pt A): 435-445, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30466899

RESUMEN

PURPOSE: To establish a predictive model for surgical resection of invasive pulmonary adenocarcinoma (IPA) presenting as ground-glass nodules (GGNs) based on a radiomics nomogram. METHODS: The CT images of 239 patients with GGNs were collected, of which 160 cases were included in the training set to construct the predictive model and 79 cases were included in the validation set to verify the established predictive model. The least absolute shrinkage and selection operator algorithm was used to select the radiomic features and construct the radiomics tagging. The predictive model for the surgical resection of IPA was constructed using the radiomics nomogram. RESULTS: The presence of IPA showed significant correlations with seven radiomics features (P < .01), which were the independent predictors. The predictive model constructed using the radiomics features performed well on the training set (area under the curve [AUC] 0.792, 95% confidence interval [CI]: 0.720-0.864) and the validation set (AUC 0.773, 95% CI: 0.668-0.877). The predictive model constructed using the clinical information alone was relatively less effective (AUC 0.711, 95% CI: 0.634-0.787). The predictive model constructed by integrating the radiomics features into the clinical information using the radiomics nomogram showed the best predictive ability and calibration in the training set (AUC 0.831, 95% CI: 0.765-0.897) and the validation set (AUC 0.816, 95% CI: 0.724-0.909). Decision curve analysis showed that radiomics nomogram has a certain clinical value. CONCLUSION: The predictive model for surgical resection of IPA constructed by integrating the radiomics features and the clinical information based on the radiomics nomogram can help clinicians control the operative node and reduce the occurrence of overtreatment.


Asunto(s)
Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/cirugía , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Nódulos Pulmonares Múltiples/cirugía , Invasividad Neoplásica/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Nódulos Pulmonares Múltiples/patología , Invasividad Neoplásica/patología , Nomogramas , Valor Predictivo de las Pruebas
7.
Radiol Med ; 124(1): 8-13, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30191447

RESUMEN

PURPOSE: To perform contrast analysis of the relationship between high-resolution computed tomography (HRCT) signs and new pathologic classification of small GGNs-like lung adenocarcinoma. MATERIALS AND METHODS: The HRCT data from 145 pathologically confirmed cases of small GGNs of lung adenocarcinoma were analysed retrospectively. The 145 cases of GGNs were divided into pre-invasive (PI) group (n = 46), micro-invasive adenocarcinoma (MIA) group (n = 48), and invasive adenocarcinoma (IAC) group (n = 51). HRCT imaging sign of GGNs in each group was assessed and compared. RESULTS: Significant differences in GGN size were found among the three groups (P < 0.05). The presence of a tumour-lung interface in the MIA and IAC groups was significantly higher than that in the PI group (P < 0.05), but no significant difference was found between the MIA and IAC groups. The presence of a pleural indentation sign in the IAC group was significantly higher than that in the other two groups (P < 0.05), but no significant difference was noted between the latter two groups. Significant differences were found in the lobulated and spicule signs among the three groups (P < 0.05). The presence of a microvascular sign in the MIA and IAC groups was significantly higher than that in the PI group (P < 0.05). No significant difference was found in the GGN density, vacuole sign, air bronchus sign and notch sign among the three groups. CONCLUSIONS: The HRCT signs of GGNs could be used to differentiate among pre-invasive lesions, micro-invasive lesions and invasive lung adenocarcinoma.


Asunto(s)
Adenocarcinoma del Pulmón/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Invasividad Neoplásica/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Nódulos Pulmonares Múltiples/patología , Nódulos Pulmonares Múltiples/cirugía , Invasividad Neoplásica/patología , Interpretación de Imagen Radiográfica Asistida por Computador , Estudios Retrospectivos
8.
Korean J Radiol ; 18(3): 470-475, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28458599

RESUMEN

OBJECTIVE: To evaluate the validity of two abbreviated protocols (AP) of MRI in breast cancer screening of dense breast tissue. MATERIALS AND METHODS: This was a retrospective study in 356 participants with dense breast tissue and negative mammography results. The study was approved by the Nanjing Medical University Ethics Committee. Patients were imaged with a full diagnostic protocol (FDP) of MRI. Two APs (AP-1 consisting of the first post-contrast subtracted [FAST] and maximum-intensity projection [MIP] images, and AP-2 consisting of AP-1 combined with diffusion-weighted imaging [DWI]) and FDP images were analyzed separately, and the sensitivities and specificities of breast cancer detection were calculated. RESULTS: Of the 356 women, 67 lesions were detected in 67 women (18.8%) by standard MR protocol, and histological examination revealed 14 malignant lesions and 53 benign lesions. The average interpretation time of AP-1 and AP-2 were 37 seconds and 54 seconds, respectively, while the average interpretation time of the FDP was 3 minutes and 25 seconds. The sensitivities of the AP-1, AP-2, and FDP were 92.9, 100, and 100%, respectively, and the specificities of the three MR protocols were 86.5, 95.0, and 96.8%, respectively. There was no significant difference among the three MR protocols in the diagnosis of breast cancer (p > 0.05). However, the specificity of AP-1 was significantly lower than that of AP-2 (p = 0.031) and FDP (p = 0.035), while there was no difference between AP-2 and FDP (p > 0.05). CONCLUSION: The AP may be efficient in the breast cancer screening of dense breast tissue. FAST and MIP images combined with DWI of MRI are helpful to improve the specificity of breast cancer detection.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Mama/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Adulto , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Femenino , Humanos , Anamnesis , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad
9.
Immunopharmacol Immunotoxicol ; 39(1): 37-44, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28004985

RESUMEN

Cyclophosphamide (CY) is a DNA alkylating agent, which is widely used with other chemotherapy drugs in the treatment of various types of cancer. It can be used not only as a chemotherapeutic but also as an immunomodulatory agent to inhibit IL-10 expression and T regulatory cells (Tregs). Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts in the tumor microenvironment. Immunotherapy based on FAPα, as a tumor stromal antigen, typically induces specific immune response targeting the tumor microenvironment. This study evaluated the efficacy of a previously unreported CY combination strategy to enhance the limited anti-tumor effect of a DNA vaccine targeting FAPα. The results suggested CY administration could promote the percentage of splenic CD8+ T cells and decrease the proportion of CD4 + CD25 + Foxp3+ Tregs in spleen. In tumor tissues, levels of immunosuppressive cytokines including IL-10 and CXCL-12 were also reduced. Meanwhile, the CY combination did not impair the FAPα-specific immunity induced by the DNA vaccine and further reduced tumor stromal factors. Most importantly, FAP-vaccinated mice also treated with CY chemotherapy showed a marked suppression of tumor growth (inhibition ratio =80%) and a prolongation of survival time. Thus, the combination of FAPα immunotherapy and chemotherapy with CY offers new insights into improving cancer therapies.


Asunto(s)
Vacunas contra el Cáncer/farmacología , Ciclofosfamida/farmacocinética , Gelatinasas/farmacología , Inmunidad Celular/efectos de los fármacos , Neoplasias Mamarias Experimentales/terapia , Proteínas de la Membrana/farmacología , Serina Endopeptidasas/farmacología , Vacunas de ADN/farmacocinética , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Vacunas contra el Cáncer/inmunología , Endopeptidasas , Femenino , Gelatinasas/inmunología , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/patología , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Serina Endopeptidasas/inmunología , Vacunas de ADN/inmunología
10.
Acad Radiol ; 24(3): 316-320, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27916594

RESUMEN

RATIONALE AND OBJECTIVES: The study aimed to evaluate the usefulness of an abbreviated protocol (AP) of magnetic resonance imaging (MRI) in comparison to a full diagnostic protocol (FDP) of MRI in the breast cancer screening with dense breast tissue. MATERIALS AND METHODS: There are 478 female participants with dense breast tissue and negative mammography results, who were imaged with MRI using AP and FDP. The AP and FDP images were analyzed separately, and the sensitivity and specificity of breast cancer detection were calculated. The chi-square test and receiver operating characteristics curves were used to assess the breast cancer diagnostic capabilities of the two protocols. RESULTS: Sixteen cases of breast cancer from 478 patients with dense breasts were detected using the FDP method, with pathologic confirmation of nine cases of ductal carcinoma in situ, six cases of invasive ductal carcinoma, and one case of mucinous carcinoma. Fifteen cases of breast cancer were successfully screened using the AP method. The sensitivity showed no obvious significant difference between AP and FDP (χ2 = 0.592, P = 0.623), but the specificity showed a statistically significant difference (χ2 = 4.619, P = 0.036). The receiver operating characteristics curves showed high efficacy of both methods in the detection of breast cancer in dense breast tissue (the areas under the curve were 0.931 ± 0.025 and 0.947 ± 0.024, respectively), and the ability to diagnose breast cancer was not statistically significantly different between the two methods. CONCLUSIONS: The AP of MRI may improve the detection rate of breast cancer in dense breast tissue, and it may be useful in efficient breast cancer screening.


Asunto(s)
Densidad de la Mama/fisiología , Neoplasias de la Mama/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Mamografía/métodos , Adulto , Anciano , Mama/diagnóstico por imagen , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
11.
Int J Oral Sci ; 8(4): 246-253, 2016 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-27660048

RESUMEN

The aim of this study was to evaluate and compare the colour stabilities of three types of orthodontic clear aligners exposed to staining agents in vitro. Sixty clear orthodontic aligners produced by three manufacturers (Invisalign, Angelalign, and Smartee) were immersed in three staining solutions (coffee, black tea, and red wine) and one control solution (distilled water). After 12-h and 7-day immersions, the aligners were washed in an ultrasonic cleaner and measured with a colourimeter. The colour changes (ΔE*) were calculated on the basis of the Commission Internationale de I'Eclairage L*a*b* colour system (CIE L*a*b*), and the results were then converted into National Bureau of Standards (NBS) units. Fourier transformation infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM) were conducted to observe the molecular and morphologic alterations to the aligner surfaces, respectively. The three types of aligners exhibited slight colour changes after 12 h of staining, with the exception of the Invisalign aligners stained with coffee. The Invisalign aligners exhibited significantly higher ΔE* values (ranging from 0.30 to 27.81) than those of the Angelalign and Smartee aligners (ΔE* values ranging from 0.33 to 1.89 and 0.32 to 1.61, respectively, P<0.05). FT-IR analysis confirmed that the polymer-based structure of aligners did not exhibit significant chemical differences before and after the immersions. The SEM results revealed different surface alterations to the three types of aligner materials after the 7-day staining. The three types of aesthetic orthodontic appliances exhibited colour stability after the 12-h immersion, with the exception of the Invisalign aligners stained by coffee. The Invisalign aligners were more prone than the Angelalign and Smartee aligners to pigmentation. Aligner materials may be improved by considering aesthetic colour stability properties.


Asunto(s)
Café , Color , , Decoloración de Dientes , Ensayo de Materiales , Espectroscopía Infrarroja por Transformada de Fourier
12.
Cell Immunol ; 310: 89-98, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27545090

RESUMEN

Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts (CAFs), which are the main type of cells in the tumor microenvironment. CAFs exert immunosuppressive activity, which can weaken the effects of cancer immunotherapy and mainly account for poor outcomes with therapeutic vaccines. To better target and destroy CAFs, a FAPα vaccine using a modified vaccinia ankara (MVA) vector was constructed and used with a DNA vaccine reported in our previous work for heterologous prime-boost immunizations in mice. This strategy to generate anti-tumor immunity partly reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses in a preventive model, but the effect required improvement. Combining the FAPα-based cancer vaccines (CpVR-FAP/MVA-FAP) with cyclophosphamide (CY), which can be used not only as a chemotherapeutic but also an immunomodulatory agent to promote a shift from immunosuppression to immunopotentiation, resulted in markedly enhanced tumor growth inhibition compared with the CpVR-FAP/MVA-FAP group. This strategy achieved synergistic effects in a therapeutic model by improving the tumor inhibition rate by 2.5-fold (90.2%), significantly enhancing cellular immunity and prolonging the survival of 4T1 tumor-bearing mice by 35% compared with the PBS group. Furthermore, CAFs, stromal factors and immunosuppressive factors such as IL-10 and Tregs were also markedly decreased by the CY combination. These results indicated that FAPα-targeted MVA boosting in combination with CY is an effective approach to improving specific anti-tumor immune responses through overcoming immunosuppression. This study may offer important advances in research on clinical cancer immunotherapies by modulating immunosuppressive factors.


Asunto(s)
Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/inmunología , Ciclofosfamida/uso terapéutico , Fibroblastos/fisiología , Gelatinasas/inmunología , Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Proteínas de la Membrana/inmunología , Serina Endopeptidasas/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Procesos de Crecimiento Celular , Línea Celular Tumoral , Terapia Combinada , Modelos Animales de Enfermedad , Endopeptidasas , Femenino , Gelatinasas/genética , Vectores Genéticos , Inmunización Secundaria , Interleucina-10/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Serina Endopeptidasas/genética , Microambiente Tumoral , Vacunas de ADN , Vaccinia/genética
13.
Vaccine ; 34(38): 4526-4535, 2016 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-27498213

RESUMEN

Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts (CAFs) of more than 90% of malignant epithelia carcinomas. CAFs are the main type of cells in the tumor microenvironment which offer nutrition and protection to the tumor and regulate immunosuppression. To eliminate CAFs, a vaccine targeting FAPα may be used with a heterologous prime-boost strategy to enhance the FAPα-specific cellular immunity. Here, a FAP vaccine using a recombinant adenovirus (rAd) vector was constructed as well as a DNA vaccine reported in our previous work. Although the DNA prime-rAd boost strategy enhanced FAPα-specific immune responses, improvement of anti-tumor immunity effects was not observed. Examination of immunosuppressive factors revealed that high expression of the IL-10 cytokine was considered the main cause of the failure of the prime-boost strategy. However, heterologous vaccination in combination with a low-dose of cyclophosphamide (CY), which was reported to reduce IL-10 production and promote a shift from immunosuppression to immunopotentiation, resulted in enhanced effects in terms of numbers of effector T cells and tumor growth inhibition rates, compared to the CY alone or DNA alone group. Tumor growth was inhibited markedly when the prime-boost strategy was combined with CY in both the prophylactic and therapeutic settings and the survival time of 4T1 tumor bearing mice was also prolonged significantly. With the reduction of IL-10, enhancement of the anti-tumor effect by the prime-boost strategy was observed. These results suggest that FAPα-targeted rAd boosting in combination with CY is an attractive approach to overcoming immunosuppression in cancer vaccines.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Ciclofosfamida/farmacología , Gelatinasas/inmunología , Interleucina-10/antagonistas & inhibidores , Proteínas de la Membrana/inmunología , Neoplasias Experimentales/terapia , Serina Endopeptidasas/inmunología , Adenoviridae , Animales , Línea Celular Tumoral , Endopeptidasas , Femenino , Fibroblastos/inmunología , Vectores Genéticos , Inmunidad Celular , Inmunización Secundaria , Ratones , Ratones Endogámicos BALB C , Linfocitos T/inmunología , Microambiente Tumoral , Vacunas de ADN/inmunología
14.
Cancer Immunol Immunother ; 65(5): 613-24, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27020681

RESUMEN

Fibroblast activation protein α (FAPα) is a tumor stromal antigen overexpressed by cancer-associated fibroblasts (CAFs). CAFs are genetically more stable compared with the tumor cells and immunosuppressive components of the tumor microenvironment, rendering them excellent targets for cancer immunotherapy. DNA vaccines are widely applied due to their safety. To specifically destroy CAFs, we constructed and examined the immunogenicity and anti-tumor immune mechanism of a DNA vaccine expressing human FAPα. This vaccine successfully reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses which could kill CAFs, and the decrease in FAPα-expressing CAFs resulted in markedly attenuated expression of collagen I and other stromal factors that benefit the tumor progression. Based on these results, a DNA vaccine targeting human FAPα may be an attractive and effective cancer immunotherapy strategy.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Gelatinasas/inmunología , Neoplasias Mamarias Experimentales/inmunología , Proteínas de la Membrana/inmunología , Serina Endopeptidasas/inmunología , Microambiente Tumoral/inmunología , Vacunas de ADN/inmunología , Animales , Vacunas contra el Cáncer/farmacología , Línea Celular Tumoral , Colágeno Tipo I/inmunología , Colágeno Tipo I/metabolismo , Endopeptidasas , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/inmunología , Fibroblastos/metabolismo , Gelatinasas/genética , Gelatinasas/metabolismo , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos BALB C , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Vacunación/métodos , Vacunas de ADN/farmacología
15.
Int Immunopharmacol ; 17(1): 9-17, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23624214

RESUMEN

As an ideal tumor antigen, survivin has been widely used for tumor immunotherapy. Nevertheless, no effective protein vaccine targeting survivin has been reported, which may be due to its poor ability to induce cellular immunity. Thus, a suitable immunoadjuvant and optimized immunization strategy can greatly enhance the cellular immune response to this protein vaccine. DDA/MPL (monophosphoryl lipid A formulated with cationic dimethyldioctadecylammonium) has been reported to enhance the antigen uptake and presentation to T cells as an adjuvant. Meanwhile, a heterologous prime-boost strategy can enhance the cellular immunity of a protein vaccine by applying different antigen-presenting systems. Here, DDA/MPL and an adenovirus prime-protein boost strategy were applied to enhance the specific anti-tumor immunity of a truncated survivin protein vaccine. Antigen-specific IFN-γ-secreting T cells were increased by 10-fold, and cytotoxic T lympohocytes (CTLs) were induced effectively when the protein vaccine was combined with the DDA/MPL adjuvant. Meanwhile, the Th1 type cellular immune response was strongly enhanced and tumor inhibition was significantly increased by 96% with the adenovirus/protein prime-boost strategy, compared to the protein homologous prime-boost strategy. Moreover, this adjuvanted heterologous prime-boost strategy combined with oxaliplatin could significantly enhance the efficiency of tumor growth inhibition through promoting the proliferation of splenocytes. Thus, our results provide a novel vaccine strategy for cancer therapy using an adenovirus prime-protein boost strategy in a murine melanoma model, and its combination with oxaliplatin may further enhance the anti-tumor efficacy while alleviating side effects of the drug.


Asunto(s)
Proteínas Inhibidoras de la Apoptosis/metabolismo , Lípido A/análogos & derivados , Melanoma/terapia , Compuestos de Amonio Cuaternario/farmacología , Adyuvantes Inmunológicos , Animales , Vacunas contra el Cáncer , Línea Celular , Proliferación Celular , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Lípido A/administración & dosificación , Lípido A/farmacología , Melanoma/inmunología , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales , Compuestos Organoplatinos , Oxaliplatino , Compuestos de Amonio Cuaternario/administración & dosificación , Organismos Libres de Patógenos Específicos , Survivin , Subgrupos de Linfocitos T
16.
Asian Pac J Cancer Prev ; 13(11): 5557-62, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23317217

RESUMEN

AIM: The aim of this study was to investigate the frequency and correlation between auto-antibodies to survivin and MUC1 variable number tandem repeats (VNTR) in colorectal cancer (CRC), which can provide valuable information for the design of immunotherapeutic vaccines for this disease. METHODS: Enzyme-linked immunosorbent assays (ELISA) were used to examine the level of auto-antibodies against survivin and MUC1 VNTR in the serum of 135 CRC patients and 95 healthy volunteers. RESULTS: Using mean absorbance+2 standard deviations (SD) of the healthy samples as a cut-off value, the positive rates of survivin and MUC1 VNTR auto- antibodies in CRC were 31.1% and 18.5%, respectively. Altogether, the survivin and MUC1 VNTR positive samples accounted for 36.3% of the CRC patients, and 7.4% were positive for both. CONCLUSION: A significant positive correlation was found between levels of specific antibodies against survivin and MUC1 VNTR in the serum of CRC patients (r=0.3652, P<0.0001), suggesting that vaccines against both targets would elicit immune responses more effectively.


Asunto(s)
Adenocarcinoma/diagnóstico , Autoanticuerpos/sangre , Neoplasias Colorrectales/diagnóstico , Proteínas Inhibidoras de la Apoptosis/inmunología , Repeticiones de Minisatélite/inmunología , Adenocarcinoma/sangre , Adenocarcinoma/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Estudios de Casos y Controles , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mucina-1 , Proteínas Recombinantes/inmunología , Survivin
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