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1.
Cancer Immunol Immunother ; 73(8): 144, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38832979

RESUMEN

BACKGROUND: The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low programmed death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial. METHODS: We conducted a retrospective analysis of patients with G/GEJ adenocarcinoma who had undergone first-line treatment with PD-1 inhibitors plus chemotherapy between October 2017 and May 2022. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). SPSS software V27.0 was used for data analysis. RESULTS: Of 345 enrolled patients, 290 had measurable lesions. The overall ORR was 59.3%. PD-L1 status was available in 171 patients, and 67.8% of them were considered as low PD-L1 expression level (combined positive score (CPS) < 5). Patients with PD-L1 CPS < 5 showed a lower response rate (51.1% vs 70.8%, P = 0.024) and a worse PFS (P = 0.009) compared to those with PD-L1 CPS ≥ 5. In the PD-L1 low-expression cohort, patients with non-diffuse type, GEJ cancer, synchronous metastasis, distant lymph node metastasis, liver metastasis, non-peritoneal metastasis, and HER2 positive were significantly associated with higher response rates to PD-1 inhibitors plus chemotherapy (P < 0.05). The presence of peritoneal metastasis (P = 0.028) and diffuse type (P = 0.046) were identified as independent predictors of poor PFS in multivariate analysis of the PD-L1 CPS < 5 subgroup. When evaluated for correlation with overall survival (OS) in the PD-L1 low-expression subgroup, peritoneal metastasis was found to be the only independent prognostic factor of an increased risk of death (hazard ratio: 2.31, 95% CI 1.09-4.90; P = 0.029). CONCLUSIONS: PD-L1 CPS ≥ 5 is significantly associated with improved response and extended PFS in G/GEJ cancer patients treated with a combination of PD-1 inhibitors and chemotherapy. Specific subgroups within the low PD-L1-expressing population, such as those with non-diffuse-type tumors and without peritoneal metastases, may also benefit from immunotherapy combined with chemotherapy.


Asunto(s)
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Biomarcadores de Tumor , Neoplasias Esofágicas , Unión Esofagogástrica , Inhibidores de Puntos de Control Inmunológico , Neoplasias Gástricas , Humanos , Masculino , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Femenino , Persona de Mediana Edad , Unión Esofagogástrica/patología , Unión Esofagogástrica/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Anciano , Estudios Retrospectivos , Biomarcadores de Tumor/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anciano de 80 o más Años , Pronóstico
2.
Cancer Cell Int ; 24(1): 181, 2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38790057

RESUMEN

BACKGROUND: Immune checkpoint inhibitors are approved for the treatment of various tumors, but the response rate is not satisfactory in certain malignancies. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ligase activity is involved in the regulation of immune responses. APG-1387 is a novel second mitochondria-derived activator of caspase (Smac) mimetic IAP inhibitor. The aim of this study was to explore the synergistic effect of APG-1387 when combined with anti-PD-1 antibody in a preclinical setting. METHODS: We utilized syngeneic mouse models of ovarian cancer (ID8), colon cancer (MC38), malignant melanoma (B16), and liver cancer (Hepa1-6) to assess the combination effect of APG-1387 and anti-PD-1 antibody, including immune-related factors, tumor growth, and survival. MSD V-PLEX validated assays were used to measure in vitro and in vivo cytokine release. RESULTS: In ID8 ovarian cancer and MC38 colon cancer models, APG-1387 and anti-PD1 antibody had synergistic antitumor effects. In the MC38 model, the combination of APG-1387 and anti-PD-1 antibody significantly inhibited tumor growth (P < 0.0001) and increased the survival rate of tumor-bearing animals (P < 0.001). Moreover, we found that APG-1387 upregulated tumor-infiltrating CD3 + NK1.1 + cells by nearly 2-fold, by promoting tumor cell secretion of IL-12. Blocking IL-12 secretion abrogated the synergistic effects of APG-1387 and anti-PD-1 antibody in both MC38 and ID8 models. CONCLUSIONS: APG-1387 has the potential to turn "cold tumors" into hot ones by recruiting more CD3 + NK1.1 + cells into certain tumors. Based on these and other data, the safety and therapeutic effect of this combination will be investigated in a phase 1/2 trial in patients with advanced solid tumors or hematologic malignancies (NCT03386526).

3.
Cancer Sci ; 113(10): 3330-3346, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35792657

RESUMEN

Colon cancer is the third most common cancer and the second leading cause of cancer-related death worldwide. Dysregulated RNA splicing factors have been reported to be associated with tumorigenesis and development in colon cancer. In this study, we interrogated clinical and RNA expression data of colon cancer patients from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) database. Genes regulating RNA splicing correlated with survival in colon cancer were identified and a risk score model was constructed using Cox regression analyses. In the risk model, RNA splicing factor peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1) is correlated with a good survival outcome, whereas Cdc2-like kinase 1(CLK1), CLK2, and A-kinase anchor protein 8-like (AKAP8L) with a bad survival outcome. The risk model has a good performance for clinical prognostic prediction both in the TCGA cohort and the other two validation cohorts. In the tumor microenvironment (TME) analysis, the immune score was higher in the low-risk group, and TME-related pathway gene expression was also higher in low-risk group. We further verified the mRNA and protein expression levels of these four genes in the adjacent nontumor, tumor, and liver metastasis tissues of colon cancer patients, which were consistent with bioinformatics analysis. In addition, knockdown of AKAP8L can suppress the proliferation and migration of colon cancer cells. Animal studies have also shown that AKAP8L knockdown can inhibit tumor growth in colon cancer in vivo. We established a prognostic risk model for colon cancer based on genes related to RNA splicing regulation and uncovered the role of AKAP8L in promoting colon cancer progression.


Asunto(s)
Neoplasias del Colon , Regulación Neoplásica de la Expresión Génica , Proteínas de Anclaje a la Quinasa A/genética , Proteínas de Anclaje a la Quinasa A/metabolismo , Neoplasias del Colon/genética , Expresión Génica , Humanos , Receptores Activados del Proliferador del Peroxisoma/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Pronóstico , Empalme del ARN/genética , Factores de Empalme de ARN/genética , ARN Mensajero/genética , Microambiente Tumoral
4.
Cancer Cell Int ; 22(1): 90, 2022 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-35189899

RESUMEN

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a severe disease with high mortality, and is associated with poor prognosis and frequent lymphatic metastasis. Therefore, prognostic indicators for ESCC are urgently needed. A-kinase anchor-protein 8-like (AKAP8L) is a member of the A kinase anchor-protein (AKAPs) family and is overexpressed in many cancers. However, the role of AKAP8L in ESCC remains unclear. The aim of this study is to investigate the expression patterns and prognostic value of AKAP8L in ESCC. METHODS: The mRNA expression of AKAP8L was analyzed from the dataset of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry was applied to detect the AKAP8L expression in tissue microarray. Pearson's chi-square test was carried out for the correlation analysis of clinicopathological features and AKAP8L expression. The prognostic significance of clinicopathological features and AKAP8L expression was determined by univariate and multivariate Cox hazard models. Kaplan-Meier survival curve was used for survival analysis. RESULTS: We found that the mRNA level of AKAP8L was higher in tumor tissues than in adjacent tissues in TCGA and GEO dataset. High AKAP8L expression was associated with poor overall survival (OS) in ESCC patients (p = 0.0039). Besides, AKAP8L expression was highly expressed in patients with lymph node metastasis detected by ESCC tissue microarray (p = 0.0014). The comparison of the different clinicopathological features of ESCC between high and low AKAP8L expression groups revealed that high AKAP8L expression was related to lymph node stage (p = 0.041). Kaplan-Meier survival analysis revealed that high AKAP8L expression indicates an unfavorable progression-free survival (PFS) and OS in ESCC patients (p < 0.0001). Univariate and multivariate analyses confirmed that AKAP8L was an independent prognostic factor for PFS and OS in ESCC (p = 0.003 and p < 0.0001). CONCLUSIONS: In conclusion, this study demonstrated that high expression of AKAP8L is associated with poor prognosis of ESCC and can be considered an independent risk factor for ESCC.

5.
BMC Cancer ; 22(1): 752, 2022 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-35820889

RESUMEN

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations. METHODS: KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic-pharmacodynamic correlations and the mechanism of actions driving drug combination synergy. RESULTS: In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449. CONCLUSIONS: Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK+ NSCLC refractory to earlier-generation ALK inhibitors. TRIAL REGISTRATION: Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Ováricas , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Ensayos Clínicos Fase I como Asunto , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo
6.
Oncologist ; 26(7): e1161-e1170, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33844372

RESUMEN

BACKGROUND: The impact of HER2 somatic mutations in colorectal carcinoma (CRC) has not been well studied and its relationship with microsatellite instability-high (MSI-H) is yet to be fully elucidated. MATERIALS AND METHODS: From February 2017 to February 2020, the data of patients with CRC who underwent next-generation sequencing and had detailed record of clinicopathological information were investigated. HER2 alteration and its relationship with MSI-H were analyzed. RESULTS: Among 731 patients who underwent sequencing, 55 patients (7.5%) had HER2 alteration, including 29 (4.0%) with HER2 somatic mutations, 24 (3.3%) with HER2 gene amplification, and 2 patients (0.2%) with both HER2 mutations and amplification. R678Q was the most common mutated kinase domain, and no HER2 kinase domain in-frame insertions/deletions were found in HER2 mutated cases. MSI-H was found in 5.2% of our cohort and 36.8% of MSI-H patients had HER2 mutation. For HER2 mutated cases, 48.3% were MSI-H, whereas none of the HER2 amplification cases were MSI-H. MSI-H patients with HER2 mutation had significantly worse median progression-free survival for programmed death-1 (PD-1) antibody than those without HER2 alteration (p = .036). CONCLUSION: High MSI-H rate was found in HER2 mutated cases, but no MSI-H was found in HER2 amplification cases. MSI-H patients with HER2 mutated had worse progression-free survival for PD-1 antibody than those without. IMPLICATIONS FOR PRACTICE: This study highlights the high microsatellite instability-high (MSI-H) rate in HER2 mutated cases but no MSI-H in HER2 amplification cases. Moreover MSI-H patients with HER2 mutated had worse progression-free survival for programmed death-1 antibody than those without. Further research to explore the internal relationship between HER2 alteration and MSI-H is needed.


Asunto(s)
Adenocarcinoma , Neoplasias Colorrectales , Adenocarcinoma/genética , Neoplasias Colorrectales/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inestabilidad de Microsatélites , Mutación , Supervivencia sin Progresión
7.
Dig Dis Sci ; 66(2): 474-482, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32193860

RESUMEN

BACKGROUND: Liver metastasis is an indicator of unfavorable responses to immunotherapy in colorectal cancer patients. However, the difference of immune microenvironment between primary tumors and liver metastases has not been well understood. PATIENTS AND METHODS: Fifty-four colon cancer with liver metastasis patients who received resection of both primary and metastasis lesions have been analyzed. The immune score is based on the density of infiltrating immune cells (CD3+ cell, CD8+ cell, CD11b+ cell, CD11c+ cell, and CD33+ cell) in the center and margin of the tumor. The expression of immune markers between the primary tumor and hepatic metastases was analyzed using Wilcoxon's signed rank test. RESULTS: All the five markers had higher expression in tumor margins than center tumor in both primary tumor and hepatic metastases lesions. The expression of CD11c and CD11b had no difference between metastatic lesions and primary tumor. In tumor margins, except CD11b, all the other 4 markers expressed significantly higher in hepatic metastases than in primary tumor. Intra-tumor, CD3 had higher expression in primary tumor than in hepatic metastases, while CD33 had higher expression in hepatic metastases than in primary tumor. CD8+ CD3+ cells of the total CD8+ cell population in primary tumor was significantly higher than in hepatic metastases (36.42% vs. 24.88%, p = 0.0069). CONCLUSIONS: The immune microenvironment between primary tumor and hepatic metastasis is different. More immunosuppressing cells in liver may partially explain why immunotherapy in colon cancer is less effective with liver metastatic disease.


Asunto(s)
Biomarcadores , Neoplasias del Colon/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Microambiente Tumoral/fisiología , Neoplasias del Colon/patología , Femenino , Humanos , Neoplasias Hepáticas/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Márgenes de Escisión , Persona de Mediana Edad , Estudios Retrospectivos , Linfocitos T/inmunología , Linfocitos T/patología
8.
BMC Cancer ; 20(1): 1, 2019 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-31892356

RESUMEN

BACKGROUND: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family proteins may be a new strategy for the treatment of malignant lymphoma. In this study, we investigate the antitumor effect and cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, in DCBCL and Burkitt lymphoma cells. METHODS: The CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using a caspase-3/caspase-9 activity kit. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. RESULTS: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells that harbor high expression of Bcl-2 and Bcl-xL in vitro and has a synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interactions of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, and PUMA/Bcl-2 and induces conformational changes in the Bax protein, which result in the activation of Bax and release of cytochrome c, activate caspase - 9, - 3, and - 7 and finally induce cell apoptosis. Furthermore, our data demonstrate that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. CONCLUSIONS: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo and provides promising preclinical data for the further development of BM-1197 in malignant lymphoma.


Asunto(s)
Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Linfoma/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Línea Celular Tumoral , Humanos , Células Jurkat , Masculino , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Support Care Cancer ; 23(7): 1933-9, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25492636

RESUMEN

PURPOSE: The aim of our study is firstly to evaluate the prevalence and prognostic value of nutrition risk in gastric cancer patients and secondly to explore whether the nutrition support can prolong the survival of advanced gastric cancer patients. METHODS: It contained two study periods. In the first period, we prospectively evaluated the nutritional risk of gastric adenocarcinoma patients from 2009 to 2011 using the method of European Nutritional Risk Screening (NRS) 2002. The Kaplan-Meier method and log-rank test were used to evaluate the prognostic value of high nutrition risk. The second period was between 2012 and 2013. We prospectively gave the nutrition support to stage IV gastric cancer patients whose NRS is ≥3. RESULTS: There were 830 patients in the first period, 50.7% patients with a NRS ≥ 3. Patients with NRS ≥ 3 presented a significantly higher percentage of stage IV diseases, elevated values of C-reactive protein, and hypoproteinemia. The median survival was significantly higher in NRS < 3 patients (31.9 vs. 25.7 months, P < 0.001). Multivariate analysis confirmed that NRS status was an independent prognostic factor. There were 347 patients in the second period. Young, male, and good response to chemotherapy were more likely to have the NRS shift to <3 after nutrition support. The median survival was 14.3 and 9.6 months for patients with and without NRS shift, respectively, P = 0.001. CONCLUSIONS: NRS ≥ 3 was an independent adverse prognostic factor in gastric cancer patients. For stage IV patients whose NRS ≥ 3, the nutrition support might be helpful to improve the prognosis.


Asunto(s)
Adenocarcinoma/dietoterapia , Adenocarcinoma/tratamiento farmacológico , Apoyo Nutricional/métodos , Neoplasias Gástricas/dietoterapia , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Proteína C-Reactiva/metabolismo , Femenino , Humanos , Hipoproteinemia/metabolismo , Masculino , Persona de Mediana Edad , Estado Nutricional , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Neoplasias Gástricas/metabolismo , Análisis de Supervivencia
10.
Tumour Biol ; 35(5): 4369-75, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24515655

RESUMEN

The value of maintenance therapy after first-line chemotherapy has been verified in lung cancer and colorectal cancer, however, in gastric cancer, the role of maintenance therapy is still waiting for an answer. The aim of this study is to evaluate the efficacy and safety of capecitabine as maintenance treatment after first-line chemotherapy in advanced gastric adenocarcinoma patients in China. Specimens of patients with advanced gastric adenocarcinoma who were given 6 cycles of oxaliplatin and capecitabine (Xelox for short) as first-line chemotherapy, without disease progression and with grade 2 or higher neuropathy, were collected for analysis. Among them, 64 patients received capecitabine as maintenance (group A) and 222 patients without maintenance as group B. Survival analysis was performed with a Cox regression model. Grades 3-4 adverse events were uncommon; hematologic toxicity was infrequent (5%) and consistently mild in the phase of maintenance treatment. The median progression-free survival (PFS) was 11.4 months [95% confidence interval (CI), 10.2-12.6 months] for group A patients, while it was 7.1 months (95% CI, 6.1-8.0 months) for patients in group B, P < 0.001. The multivariated analysis showed that the maintenance treatment was an independent prognostic factor in advanced gastric adenocarcinoma patients. The style of first-line treatment-maintenance therapy (Xelox-X) was active and feasible for advanced gastric adenocarcinoma patients who had suffered from grade 2 or higher level of neuropathy.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Oxaloacetatos , Estudios Prospectivos , Neoplasias Gástricas/mortalidad
11.
BMC Cancer ; 14: 823, 2014 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-25380654

RESUMEN

BACKGROUND: Lauren-classification and human epidermal growth factor receptor 2 (HER2) status are two important pathological features of gastric cancer patients. The prognostic value of HER2 in gastric cancer remains controversial. Intestinal type gastric cancer has better prognosis and higher HER2 positive proportion. What is the interaction between these two factors? We hypothesized that a combination of Lauren-classification and human epidermal growth factor receptor 2 (HER2) status (L-H status) might be more meaningful than either factor alone. METHODS: We collected 838 gastric cancer patients at all stages who had received treatment in our cancer center. This study was registered in the website of ClinicalTrials.Gov, with the number NCT01927146. We divided the patients into six groups according to their L-H status: Group A, HER2 negative and intestinal type; Group B, HER2 positive and intestinal type; Group C, HER2 negative and diffuse type; Group D, HER2 positive and diffuse type; Group E, HER2 negative and mixed type; and Group F, HER2 positive and mixed type. RESULTS: Diffuse type and intestinal type accounted for 51.0% and 33.9%, respectively. The proportion of HER2 positive patients was 11.2%, 25.4%, 2.1% and 10.2% in the whole patient group, intestinal, diffuse and mixed type, respectively. Median overall survival was 34.0 months, 25.3 months, 27.6 months, 19.2 months, 25.9 months and 26.4 months in the six groups patients, P = 0.053. There was a significant difference in survival among the first four groups (P < 0.001). HER2 was an independent prognostic factor in the intestinal type and in stage I + II patients, but not in the diffuse type or stage III + IV patients. L-H status was an independent prognostic factor in patients at all stages. For the diffuse and intestinal types, the multivariate analysis showed that HER2 was not an independent prognostic factor, while Lauren classification and L-H status were. Moreover, L-H status was a better prognostic factor than the Lauren classification. CONCLUSIONS: L-H status is a prognostic factor in diffuse and intestinal type patients, but not in the mixed type. Patients with HER2 negative and intestinal type had the best survival, while patients with HER2 positive status and diffuse type had the worst survival.


Asunto(s)
Adenocarcinoma/química , Adenocarcinoma/clasificación , Receptor ErbB-2/análisis , Neoplasias Gástricas/química , Neoplasias Gástricas/clasificación , Adenocarcinoma/secundario , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , China , Femenino , Gastrectomía , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/patología , Tasa de Supervivencia , Adulto Joven
12.
Front Nutr ; 11: 1328596, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38406189

RESUMEN

Previous studies have shown that transparent packaging can influence consumer behavior, but the impact on tourists' environmentally friendly purchase intentions is not well-understood. This study conducted four experiments with 1,513 participants to explore the role of transparent packaging in tourists' willingness to engage in green purchasing. Factors such as ecological concern, nature connectedness, and environmental consequences were also examined. The results showed that transparent packaging significantly enhanced tourists' purchase intentions and that ecological concern, nature connectedness, and environmental consequences had a significant influence on these intentions. These findings contribute to understanding the packaging paradox and its relationship with tourists' green purchasing behavior. The study has implications for the food retail industry and the promotion of sustainable development in scenic areas, suggesting that transparent packaging can effectively enhance tourists' purchase intentions for green products. Understanding factors like ecological concern and nature connectedness can also provide valuable insights for the industry to improve marketing strategies and promote environmentally friendly choices among tourists.

13.
Front Nutr ; 11: 1401035, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39176026

RESUMEN

This study aims to investigate the influence of psychological ownership of nutritional products on the purchase intention of high-pressure working groups, as well as the underlying mechanisms and boundary conditions of this influence. This study aims to investigate the impact of psychological ownership of nutritional products on the purchase intention of high-pressure working groups, as well as the underlying mechanisms and boundary conditions of this influence. The research contributes through the use of variance analysis, mediation models, and moderation models on data from adult participants over the age of 18, across three experiments. Experiment 1, conducted on the Credamo platform, randomly recruited 285 participants, with 148 males (51.9%) and 137 females (48.1%), and the results indicated a direct impact of psychological ownership on purchase intention. Building upon this, Experiment 2, which also utilized the Credamo platform and recruited 280 participants consisting of 136 males (48.6%) and 144 females (51.4%), further revealed the mediating role of perceived value. Experiment 3, with 265 participants randomly recruited on the Credamo platform, including 131 males (49.4%) and 134 females (50.6%), identified the moderating effect of nutritional awareness. The theoretical contribution of this study lies primarily in its in-depth exploration of the impact of psychological ownership of nutritional products. By integrating the factors of perceived value and nutritional awareness, it provides a systematic explanation for better understanding the purchase intentions of high-pressure working groups. Additionally, this study offers valuable strategies for merchants to enhance the purchase intentions of high-pressure living groups.

14.
Clin Transl Oncol ; 26(3): 765-773, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37620706

RESUMEN

BACKGROUND: Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. METHODS: HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method. RESULT: There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white, of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73 months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30 months vs.16.13 months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients.


Asunto(s)
Neoplasias Encefálicas , Neoplasias Gástricas , Humanos , Masculino , Femenino , Neoplasias Gástricas/patología , Receptor ErbB-2/metabolismo , Pronóstico , Análisis de Supervivencia , Factores de Riesgo
15.
Clin Transl Sci ; 17(9): e70021, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39228016

RESUMEN

Olverembatinib (HQP1351) is a BCR-ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug-resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open-label, 2-part, fixed-sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time-concentration curve (AUC)0-last, and AUC0-inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.


Asunto(s)
Inductores del Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Voluntarios Sanos , Itraconazol , Rifampin , Humanos , Masculino , Itraconazol/farmacocinética , Itraconazol/administración & dosificación , Itraconazol/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacología , Adulto , Rifampin/administración & dosificación , Rifampin/farmacocinética , Rifampin/farmacología , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Inductores del Citocromo P-450 CYP3A/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacología , Femenino , Adulto Joven , Citocromo P-450 CYP3A/metabolismo , Persona de Mediana Edad , Administración Oral , Área Bajo la Curva , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación
16.
Clin Cancer Res ; 30(3): 506-521, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-37971712

RESUMEN

PURPOSE: B-cell lymphoma-extra-large (BCL-xL) regulates apoptosis and is an attractive anticancer therapeutic target. However, BCL-xL inhibition also kills mature platelets, hampering clinical development. Using an innovative prodrug strategy, we have developed pelcitoclax (APG-1252), a potent, dual BCL-2 and BCL-xL inhibitor. Aims of this study were to characterize the antitumor activity and safety of pelcitoclax and explore its underlying mechanisms of action (MOA). PATIENTS AND METHODS: Cell line-derived xenograft and patient-derived xenograft (PDX) models were tested to evaluate antitumor activity and elucidate MOA. Subjects (N = 50) with metastatic small-cell lung cancer and other solid tumors received intravenous pelcitoclax once or twice weekly. Primary outcome measures were safety and tolerability; preliminary efficacy (responses every 2 cycles per RECIST version 1.1) represented a secondary endpoint. RESULTS: Pelcitoclax exhibited strong BAX/BAK‒dependent and caspase-mediated antiproliferative and apoptogenic activity in various cancer cell lines. Consistent with cell-based apoptogenic activity, pelcitoclax disrupted BCL-xL:BIM and BCL-xL:PUMA complexes in lung and gastric cancer PDX models. Levels of BCL-xL complexes correlated with tumor growth inhibition by pelcitoclax. Combined with taxanes, pelcitoclax enhanced antitumor activity by downregulating antiapoptotic protein myeloid cell leukemia-1 (MCL-1). Importantly, pelcitoclax was well tolerated and demonstrated preliminary therapeutic efficacy, with overall response and disease control rates of 6.5% and 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations and reduced platelets that were less frequent with a once-weekly schedule. CONCLUSIONS: Our data demonstrate that pelcitoclax has antitumor activity and is well tolerated, supporting its further clinical development for human solid tumors, particularly combined with agents that downregulate MCL-1.


Asunto(s)
Compuestos de Anilina , Antineoplásicos , Neoplasias Pulmonares , Linfoma de Células B , Piperidinas , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína bcl-X/metabolismo , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Proto-Oncogénicas c-bcl-2 , Antineoplásicos/efectos adversos , Apoptosis , Neoplasias Pulmonares/tratamiento farmacológico , Linfoma de Células B/tratamiento farmacológico
17.
Int Immunopharmacol ; 139: 112615, 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39032475

RESUMEN

BACKGROUND AND PURPOSE: Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied. EXPERIMENTAL: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo. KEY RESULTS: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib. CONCLUSION AND IMPLICATIONS: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.


Asunto(s)
Anilidas , Carcinoma Hepatocelular , Proliferación Celular , Neoplasias Hepáticas , Ratones Desnudos , Piridinas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína bcl-X , Animales , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Anilidas/farmacología , Anilidas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Proteína bcl-X/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ratones Endogámicos BALB C , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Masculino
18.
J Exp Clin Cancer Res ; 43(1): 248, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39215364

RESUMEN

BACKGROUND: High expression of ubiquitin ligase MDM2 is a primary cause of p53 inactivation in many tumors, making it a promising therapeutic target. However, MDM2 inhibitors have failed in clinical trials due to p53-induced feedback that enhances MDM2 expression. This underscores the urgent need to find an effective adaptive genotype or combination of targets. METHODS: Kinome-wide CRISPR/Cas9 knockout screen was performed to identify genes that modulate the response to MDM2 inhibitor using TP53 wild type cancer cells and found ULK1 as a candidate. The MTT cell viability assay, flow cytometry and LDH assay were conducted to evaluate the activation of pyroptosis and the synthetic lethality effects of combining ULK1 depletion with p53 activation. Dual-luciferase reporter assay and ChIP-qPCR were performed to confirm that p53 directly mediates the transcription of GSDME and to identify the binding region of p53 in the promoter of GSDME. ULK1 knockout / overexpression cells were constructed to investigate the functional role of ULK1 both in vitro and in vivo. The mechanism of ULK1 depletion to activate GSMDE was mainly investigated by qPCR, western blot and ELISA. RESULTS: By using high-throughput screening, we identified ULK1 as a synthetic lethal gene for the MDM2 inhibitor APG115. It was determined that deletion of ULK1 significantly increased the sensitivity, with cells undergoing typical pyroptosis. Mechanistically, p53 promote pyroptosis initiation by directly mediating GSDME transcription that induce basal-level pyroptosis. Moreover, ULK1 depletion reduces mitophagy, resulting in the accumulation of damaged mitochondria and subsequent increasing of reactive oxygen species (ROS). This in turn cleaves and activates GSDME via the NLRP3-Caspase inflammatory signaling axis. The molecular cascade makes ULK1 act as a crucial regulator of pyroptosis initiation mediated by p53 activation cells. Besides, mitophagy is enhanced in platinum-resistant tumors, and ULK1 depletion/p53 activation has a synergistic lethal effect on these tumors, inducing pyroptosis through GSDME directly. CONCLUSION: Our research demonstrates that ULK1 deficiency can synergize with MDM2 inhibitors to induce pyroptosis. p53 plays a direct role in activating GSDME transcription, while ULK1 deficiency triggers upregulation of the ROS-NLRP3 signaling pathway, leading to GSDME cleavage and activation. These findings underscore the pivotal role of p53 in determining pyroptosis and provide new avenues for the clinical application of p53 restoration therapies, as well as suggesting potential combination strategies.


Asunto(s)
Homólogo de la Proteína 1 Relacionada con la Autofagia , Piroptosis , Especies Reactivas de Oxígeno , Transducción de Señal , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Ratones , Especies Reactivas de Oxígeno/metabolismo , Animales , Regulación hacia Arriba , Mutaciones Letales Sintéticas , Femenino , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Línea Celular Tumoral , Proteína con Dominio Pirina 3 de la Familia NLR
19.
Cell Mol Immunol ; 21(1): 60-79, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38062129

RESUMEN

The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from "cold" to "hot" and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.


Asunto(s)
Dioxanos , Inhibidores de Puntos de Control Inmunológico , Terapia de Inmunosupresión , Neoplasias Pulmonares , Proteína con Dominio Pirina 3 de la Familia NLR , Nitrobencenos , Proteínas Proto-Oncogénicas c-bcl-2 , Pirroles , Macrófagos Asociados a Tumores , Animales , Ratones , Dioxanos/farmacología , Dioxanos/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Nitrobencenos/farmacología , Nitrobencenos/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/agonistas , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Pirroles/farmacología , Pirroles/uso terapéutico , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/metabolismo , Factor de Transcripción ReIA/metabolismo , Microambiente Tumoral/efectos de los fármacos , Polaridad Celular/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Humanos , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos C57BL , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/metabolismo , Terapia de Inmunosupresión/métodos
20.
Blood ; 118(15): 4140-9, 2011 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-21844567

RESUMEN

Mantle cell lymphoma (MCL) usually responds well to initial therapy but is prone to relapses with chemoresistant disease, indicating the need for novel therapeutic approaches. Inhibition of the p53 E3 ligase human homolog of the murine double minute protein-2 (HDM-2) with MI-63 has been validated as one such strategy in wild-type (wt) p53 models, and our genomic and proteomic analyses demonstrated that MI-63 suppressed the expression of the ribonucleotide reductase (RNR) subunit M2 (RRM2). This effect occurred in association with induction of p21 and cell-cycle arrest at G(1)/S and prompted us to examine combinations with the RNR inhibitor 2',2'-difluoro-2'-deoxycytidine (gemcitabine). The regimen of MI-63-gemcitabine induced enhanced, synergistic antiproliferative, and proapoptotic effects in wtp53 MCL cell lines. Addition of exogenous dNTPs reversed this effect, whereas shRNA-mediated inhibition of RRM2 was sufficient to induce synergy with gemcitabine. Combination therapy of MCL murine xenografts with gemcitabine and MI-219, the in vivo analog of MI-63, resulted in enhanced antitumor activity. Finally, synergy was seen with MI-63-gemcitabine in primary patient samples that were found to express high levels of RRM2 compared with MCL cell lines. These findings provide a framework for translation of the rational combination of an HDM-2 and RNR inhibitor to the clinic for patients with relapsed wtp53 MCL.


Asunto(s)
Antimetabolitos Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Desoxicitidina/análogos & derivados , Indoles , Linfoma de Células del Manto/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Ribonucleósido Difosfato Reductasa/biosíntesis , Compuestos de Espiro , Animales , Antimetabolitos Antineoplásicos/agonistas , Antimetabolitos Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Desoxicitidina/agonistas , Desoxicitidina/farmacología , Sinergismo Farmacológico , Fase G1/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Indoles/agonistas , Indoles/farmacología , Linfoma de Células del Manto/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Fase S/efectos de los fármacos , Compuestos de Espiro/agonistas , Compuestos de Espiro/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina
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