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1.
Mol Cancer ; 23(1): 91, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715012

RESUMO

BACKGROUND: Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are involved in the occurrence and development of a variety of tumors. The aim of this study was to investigate the effects of circ_PPAPDC1A in Osimertinib resistance in NSCLC. METHODS: Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in Osimertinib-acquired resistance tissues of NSCLC. The effect of circ_PPAPDC1A on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_PPAPDC1A/miR-30a-3p/IGF1R axis. RESULTS: The results revealed that circ_PPAPDC1A was significantly upregulated in Osimertinib acquired resistance tissues of NSCLC. circ_PPAPDC1A reduced the sensitivity of PC9 and HCC827 cells to Osimertinib and promoted cell proliferation, invasion, migration, while inhibiting apoptosis in Osimertinib-resistant PC9/OR and HCC829/OR cells, both in vitro and in vivo. Silencing circ_PPAPDC1A partially reversed Osimertinib resistance. Additionally, circ_PPAPDC1A acted as a competing endogenous RNA (ceRNA) by targeting miR-30a-3p, and Insulin-like Growth Factor 1 Receptor (IGF1R) was identified as a functional gene for miR-30a-3p in NSCLC. Furthermore, the results confirmed that circ_PPAPDC1A/miR-30a-3p/IGF1R axis plays a role in activating the PI3K/AKT/mTOR signaling pathway in NSCLC with Osimertinib resistance. CONCLUSIONS: Therefore, for the first time we identified that circ_PPAPDC1A was significantly upregulated and exerts an oncogenic role in NSCLC with Osimertinib resistance by sponging miR-30a-3p to active IGF1R/PI3K/AKT/mTOR pathway. circ_PPAPDC1A may serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients with Osimertinib resistance.


Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , MicroRNAs , RNA Circular , Receptor IGF Tipo 1 , Transdução de Sinais , Humanos , MicroRNAs/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Acrilamidas/farmacologia , RNA Circular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Compostos de Anilina/farmacologia , Linhagem Celular Tumoral , Animais , Camundongos , Apoptose , Movimento Celular/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Feminino , Indóis , Pirimidinas
2.
Eur Arch Otorhinolaryngol ; 279(9): 4541-4548, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35462579

RESUMO

PURPOSE: The aim of the present study was to investigate the predictive value of the fibrinogen/albumin ratio index (FARI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) on the prognosis of patients with operable head and neck squamous cell carcinoma (HNSCC). METHODS: A cohort of 155 operable HNSCC patients were enrolled. Laboratory and clinical data were extracted from the patients' electronic medical record. The optimal cut-off values were determined by receiver operating characteristic (ROC) curves analysis. Clinicopathological characteristics of patients were compared via Chi-square test. Survival curves were analyzed by Kaplan-Meier method. The prognostic factors were evaluated by univariate and multivariate analyses via the Cox hazards regression analysis. RESULTS: The median follow-up time was 31.7 months. An increased level of NLR was associated with later T stages, later N stages, and more advanced clinical stages(all P < 0.05). On univariate analyses, FARI, NLR, PLR, and N stage were correlated with progression-free survival (PFS) (all P < 0.05) as well as overall survival (OS) (all P < 0.05). And the clinical stage was only relevant to OS (P = 0.007). Multivariate Cox regression analysis revealed that FARI (HR 3.486, 95% CI 2.086-5.825, P < 0.001; HR 4.474, 95% CI 2.442-8.199, P < 0.001), NLR (HR 3.163, 95% CI 1.810-5.528, P < 0.001; HR 3.690, 95% CI 1.955-6.963, P < 0.001), and N stage (HR 1.718, 95% CI 1.058-2.789, P = 0.029; HR 1.777, 95% CI 1.024-3.084, P = 0.041) were independent prognostic factors for PFS and OS. CONCLUSION: Our findings indicate that FARI and NLR are effective and convenient markers for predicting prognosis in operable HNSCC patients.


Assuntos
Neoplasias de Cabeça e Pescoço , Linfócitos , Albuminas , Fibrinogênio , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Linfócitos/patologia , Neutrófilos/patologia , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia
3.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 43(11): 1209-1215, 2018 Nov 28.
Artigo em Zh | MEDLINE | ID: mdl-30643065

RESUMO

OBJECTIVE: To explore the effect of down-regulation of growth arrest and DNA damage inducible protein 45ß (GADD45ß) on the PC9 lung adenocarcinoma cells.
 Methods: GADD45ß gene siRNA sequence was designed and synthesized, which was transfected into PC9 lung adenocarcinoma cells through lentivirus transfection. Quantitative real-time PCR (qRT-PCR) and Western blot are used to examine the mRNA and protein levels of GADD45ß in PC9 cells before and after the transfection. Annexin V-allophycocyanin (APC) double-staining flow cytometry was used to detect the apoptosis level after the transfection. The intracellular DNA content after transfection was detected by flow cytometry. The percentage of the cells at each period of cell cycle was calculated, and the effect of RNA interference on the cell growth were analyzed. The effects of RNA interference on the tumor-formation ability of cells were tested by counting the number of clones. MTT assay was used to test the half maximal inhibitory concentration (IC50) of PC9 cells for gefitinib. 
 Results: The 5'-AAATCCACTTCACGCTCAT-3' sequence was identified as the effective sequence for GADD45ß gene RNA interference. The mRNA and protein expression levels of GADD45ß were markedly decreased (both P<0.05) at 48 h after transfection of GADD45ß-siRNA, which resulted in the increased apoptosis rate (P<0.05), decreased tumor clone number (P<0.05) and increased percentage of PC9 cell at the S stage and G2/M stage (P<0.05). The IC50 for gefitinib was decreased obviously (P<0.05).
 Conclusion: Down-regulation of GADD45ß can reduce the colony-forming ability of PC9 cells, promote the cell apoptosis, and enhance the sensitivity of PC9 cells to gefitinib.


Assuntos
Adenocarcinoma de Pulmão , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Regulação para Baixo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Gefitinibe/farmacologia , Humanos , RNA Interferente Pequeno
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 41(12): 1297-1304, 2016 Dec 28.
Artigo em Zh | MEDLINE | ID: mdl-28070042

RESUMO

OBJECTIVE: To investigate the effect of the jianpi-jiedu formula (JPJD) on the expression of angiogenesis-relevant genes in colon cancer.
 Methods: Crude extract was obtained from JPJD by water extract method. The effect of JPJD crude extract on colon cancer cell proliferation capacity was determined by MTT assays. The IC50 value was calculated by GraphPad Prism5 software. Affymetrix gene expression profiling chip was used to detect significant differences in expressions of genes after JPJD intervention, and pathway enrichment analysis was performed to analyze the differentially expressed genes. Ingenuity Pathway Analysis software was applied to analyze differentially expressed genes relevant to tumor angiogenesis based on mammalian target of rapamycin (mTOR) signaling pathway and then the network diagram was built. Western blot was used to verify the protein levels of key genes related to tumor angiogenesis.
 Results: JPJD crud extract inhibited the proliferation capacity in colon cancer cells. The IC50 values in 24, 48, and 72 hours after treatment were 13.060, 9.646 and 8.448 mg/mL, respectively. The results of chip showed that 218 genes significantly upgraded, and 252 genes significantly downgraded after JPJD treatment. Most of the genes were related to the function of biosynthesis, metabolism, cell apoptosis, antigen extraction, angiogenesis and so on. There were 12 differentially expressed angiogenesis genes. IPA software analysis showed that the JPJD downregulated expression of sphingomyelin phosphodiesterase 3 (SMPD3), VEGF, vascular endothelial growth factor A (VEGFA), integrin subunit alpha 1 (ITGA1), cathepsin B (CTSB), and cathepsin S (CTSS) genes, while upregulated expressions of GAB2 and plasminogen activator, urokinase receptor (PLAUR) genes in the colorectal cancer cell. Western blot results demonstrated that JPJD obviously downregulated expressions of phospho-mTOR (P-mTOR), signal transducer and activator of transcription 3 (STAT3), hypoxia inducible factor-1α (HIF-1α), and VEGF proteins, while obviously upregulated the level of phospho-P53 (P-P53) protein.
 Conclusion: JPJD may inhibit colorectal tumor angiogenesis through regulation of the mTOR-HIF-1α-VEGF signal pathway.


Assuntos
Linhagem Celular Tumoral/efeitos dos fármacos , Neoplasias Colorretais/genética , Medicamentos de Ervas Chinesas/farmacologia , Animais , Western Blotting , Catepsina B/efeitos dos fármacos , Catepsina B/metabolismo , Catepsinas/efeitos dos fármacos , Catepsinas/metabolismo , Neoplasias Colorretais/irrigação sanguínea , Regulação para Baixo , Perfilação da Expressão Gênica/métodos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Cadeias alfa de Integrinas/efeitos dos fármacos , Cadeias alfa de Integrinas/metabolismo , Neovascularização Patológica/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/efeitos dos fármacos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Esfingomielina Fosfodiesterase/efeitos dos fármacos , Esfingomielina Fosfodiesterase/metabolismo , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 41(11): 1128-1136, 2016 Nov 28.
Artigo em Zh | MEDLINE | ID: mdl-27932756

RESUMO

OBJECTIVE: To investigate the effect of jianpi-jiedu (JPJD) prescription-contained serum on colorectal cancer SW48 cell proliferation and the underlying mechanisms.
 Methods: Crude extract from JPJD was made by water extract method and the main components of crude extract from JPJD were analyzed by ultra-performance liquid phase high resolution time of flight mass spectrometry (UPLC-Q-TOF/MS). The low, medium, and high-concentration of JPJD-contained serum were prepared by the serum pharmacological method. The effect of serum containing JPJD on SW48 cell proliferation was determined by MTT assay. The cell cycle was detected by flow cytometric method. The protein levels of mammalian target of rapamycin (mTOR), phospho-mTOR, P-P53, and -P21, and the mRNA level of mTOR were examined by Western blot and RT-PCR, respectively.
 Results: Seven compounds including calycosin-7-glucoside, astragaloside, ginsenoside-Re, ginsenoside-Rb1, glycyrrhizinic acid, apigenin, atractylenolide-II were identified. MTT assays demonstrated that the SW48 cell proliferation was inhibited by medium and high concentration of JPJD-contained serum and the percentages of cells at G1 phase in SW48 cell cultured in the medium and high concentration of JPJD serum group were significantly higher than those in the control group (P<0.05). Meanwhile, the levels of mTOR mRNA and phospho-mTOR protein in the medium and high concentration of JPJD serum groups were substantially lower than those in the control group (P<0.05). Conversely, the expressions of phospho-P53 and P21 protein were significantly increased in the medium and high concentration of JPJD serum group compared with those in the control group.
 Conclusion: JPJD prescription-contained serum can inhibit SW48 cell proliferation, which may be related to mTOR-P53-P21 signaling pathways.


Assuntos
Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Animais , Apigenina , Western Blotting , Ciclo Celular , Divisão Celular , Proliferação de Células/genética , Neoplasias Colorretais , Inibidor de Quinase Dependente de Ciclina p21/efeitos dos fármacos , Citometria de Fluxo , Ginsenosídeos , Ácido Glicirrízico , Humanos , Lactonas , Fosforilação/genética , RNA Mensageiro , Saponinas , Sesquiterpenos , Transdução de Sinais , Serina-Treonina Quinases TOR/efeitos dos fármacos , Triterpenos , Proteína Supressora de Tumor p53/efeitos dos fármacos
8.
Front Pharmacol ; 15: 1275814, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38333008

RESUMO

Objective: This study aimed to investigate the potential association between biological disease-modifying antirheumatic drugs (bDMARDs) and pericarditis and uncover relevant clinical characteristics in ankylosing spondylitis (AS). Methods: Reports of pericarditis recorded in the FDA Adverse Event Reporting System (FAERS) (January 2004-December 2022) were identified through the preferred term "pericarditis." Demographic and clinical characteristics were described, and disproportionality signals were assessed through the reporting odds ratio (ROR) and information component (IC). A significant signal was detected if the lower bound of IC (IC025) was more than zero. Results: We found 1,874 reports of pericarditis with bDMARDs (11.3% of cases with fatal outcomes). Adalimumab (IC025 3.24), infliximab (IC025 4.90), golimumab (IC025 5.40), certolizumab (IC025 5.43), etanercept (IC025 3.24), secukinumab (IC025 3.97), and ustekinumab (IC025 7.61) exhibit significant disproportionality signals compared to other medications in the FAERS database. After excluding pre-existing diseases and co-treated drugs that may increase the susceptibility of pericarditis, the disproportionality signal associated with infliximab, certolizumab, etanercept, secukinumab, and ustekinumab remained strong. Pericarditis cases associated with all bDMARDs were predominantly recorded in women aged 25-65 years. Conclusion: More reports of pericarditis were detected with AS patients on bDMARDs than with other drugs in the overall database. Further studies are warranted to investigate the underlying mechanisms and identify patient-related susceptibility factors, thus supporting timely diagnosis and safe(r) prescribing of bDMARDs.

10.
Sci Rep ; 12(1): 11978, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831424

RESUMO

This retrospective study compared the efficacy and safety of nedaplatin-based chemoradiotherapy and cisplatin-based chemoradiotherapy in stage II-IVa nasopharyngeal carcinoma (NPC) patients. Patients treated with cisplatin-based or nedaplatin-based chemoradiotherapy between January 2012 and December 2015 were evaluated. Survival was estimated by the Kaplan‒Meier method and compared by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. A cohort of 538 NPC patients was enrolled. There were no significant differences in the 5-year overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), or distant metastasis-free survival (DMFS) between the cisplatin and nedaplatin groups. During the whole treatment course, patients in the cisplatin group had higher incidences of grade 3‒4 vomiting and anorexia, while patients in the nedaplatin group had higher incidences of grade 3‒4 leucopenia and mucositis. In terms of late toxicities, patients in the cisplatin group had a higher incidence of xerostomia. In multivariate analysis, T stage, N stage, and clinical stage were prognostic factors for OS, PFS, and DMFS. In subgroup analyses, nedaplatin-based chemotherapy achieved comparable treatment outcomes in specific populations stratified by age, sex, ECOG PS score and clinical stage. Cisplatin and nedaplatin are effective choices for stage II-IVa NPC patients, with a different spectrum of side effects.


Assuntos
Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Compostos Organoplatínicos , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Resultado do Tratamento
11.
Medicine (Baltimore) ; 100(36): e26750, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516487

RESUMO

ABSTRACT: To investigate the correlation between preoperative inflammatory markers, Ki-67 expression and the pathological grade of glioma, and to provide a reference for clinical prediction of glioma prognosis.A total of 45 glioma patients who underwent surgery with complete clinical and pathological data were in our hospital from January 2012 to December 2018 were enrolled. Glioma was divided into WHO grade I to IV. Forty-five healthy health examiners with matched clinical characteristics were included to the control group. Blood routine tests were recorded at admission in both the glioma and control group. The ratio of neutrophil to lymphocyte cytometry (NLR), derived neutrophil to lymphocyte ratio (dNLR) (white blood cell count - neutrophil count to neutrophil count), platelet to lymphocyte ratio (PLR) and prognostic nutritional index (PNI, serum albumin content + 5 × lymphocyte count) were calculated. The expression of Ki-67 in glioma was detected by immunohistochemistry. The relationship between the above markers, Ki-67 expression and pathological grade of glioma was evaluated with receiver operating characteristics curve analysis and Spearman correlation test. The correlation between the markers and Ki-67 were also determined.NLR, dNLR, PLR were increased in the glioma group (P < .001, <.001, .002), whereas red blood cell distribution width (RDW) was decreased (P = .009). All the glioma samples expressed Ki-67 with varying degree. Receiver operating characteristics curve analysis reveals NLR, dNLR, PLR, and RDW have significant discriminating ability in differentiating the glioma and control sample. NLR, PLR, PNI, and Ki-67 were significantly correlated with glioma pathology grade (P = .023, .006, .019, <.05), while dNLR and RDW were not associated with glioma grade. Finally, NLR and PLR were related to Ki-67 expression in glioma patients (P = .002, .022), while dNLR and RDW were not related to Ki-67 expression.Preoperative inflammatory markers NLR, PLR, PNI, and postoperative Ki-67 expression are associated with pathological grade of glioma. Detection of these markers may aid in better prediction of glioma prognosis.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Antígeno Ki-67/sangue , Linfócitos/citologia , Neutrófilos/citologia , Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade
13.
Front Oncol ; 11: 784525, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35083143

RESUMO

Cervical cancer is a highly prevalent female malignancy. Presently, cisplatin (DDP) is a first-line agent for cervical cancer chemotherapy. However, its curative effect is limited because of chemo-resistance. It has been previously reported that SOX9 targeted and activated oncogenic genes, enhancing cervical cancer cell resistance to DDP. The effects of the SOX9/lncRNA ANXA2P2/miR-361-3p/SOX9 regulatory loop on cervical cancer cell growth and resistance to DDP have been demonstrated. miR-361-3p expression was decreased in DDP-resistant cervical cancer cells and tissues. Moreover, miR-361-3p overexpression inhibited the growth of resistant cervical cancer cells and the resistance to DDP, whereas miR-361-3p inhibition exerted opposite effects. miR-361-3p inhibited SOX9 expression through binding; the effects of miR-361-3p inhibition were partially reversed by SOX9 knockdown. LncRNA ANXA2P2 expression was elevated in DDP-resistant cervical cancer cells and tissues. LncRNA ANXA2P2 inhibited miR-361-3p expression by binding, thereby upregulating SOX9. LncRNA ANXA2P2 knockdown inhibited DDP-resistant cervical cancer cell growth and resistance to DDP, whereas the effects of lncRNA ANXA2P2 knockdown were partially reversed by miR-361-3p inhibition. SOX9 expression was elevated in DDP-resistant cervical cancer cells and tissues, and SOX9 activated lncRNA ANXA2P2 transcription by binding. Collectively, SOX9, lncRNA ANXA2P2, and miR-361-3p form a regulatory loop, modulating DDP-resistant cervical cancer cell growth and response to DDP treatment.

14.
Cancer Manag Res ; 13: 1315-1322, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33633464

RESUMO

BACKGROUND: Systemic inflammation response index (SIRI) has been reported to be an effective blood-based biomarker for predicting prognosis in various kinds of cancer patients. However, the prognostic role of SIRI in advanced lung adenocarcinoma patient remains unclear. METHODS: The aim of the present study is to evaluate the prognostic role of SIRI in EGFR-mutant advanced lung adenocarcinoma patients treated with first-generation EGFR-TKIs. A total of 245 patients who received gefitinib, erlotinib, or icotinib at the Second Xiangya Hospital were retrospectively evaluated. SIRI was defined as neutrophil count×monocyte/lymphocyte count. The optimal cut-off value was determined according to receiver operation characteristic curve analysis. Characteristics of patients were compared via chi-square test or Fisher's exact test. Survivals were estimated by the Kaplan-Meier method and compared by the Log rank test. Multivariate analysis was estimated using the Cox proportional hazards model. RESULTS: It is showed that high SIRI was associated with male patient, smoker, worse ECOG PS, 19-DEL mutation. Kaplan-Meier survival analysis showed that ECOG PS, brain metastasis, SIRI were significantly correlated with progression-free survival (PFS), and gender, ECOG PS, brain metastasis, NLR and SIRI were significantly correlated with overall survival (OS). Multivariate analysis showed that SIRI and ECOG PS independently predict PFS and OS. CONCLUSION: Our findings indicate that SIRI is an effective and convenient marker for predicting prognosis in advanced EGFR-mutant lung adenocarcinoma patients treated with first-generation TKI.

15.
Expert Rev Vaccines ; 19(2): 163-173, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32174221

RESUMO

Introduction: Mutant KRAS is a genetic driver of multiple cancers that has challenged clinical anti-cancer therapeutics in the last 3 decades. Neo-antigens encoded by KRAS mutations have been identified as tumor-specific with high immunogenicity and can be used to deliver precision cancer vaccines to promote anti-tumor immune responses. KRAS mutation-based cancer vaccines have produced encouraging preclinical and clinical results. Cancer vaccines represent a promising approach to treat KRAS-driven cancers.Areas covered: In this review, we summarize the development and progress of vaccines targeting KRAS and evaluate their potential benefits and obstacles in the current landscape of therapy for KRAS-driven cancers.Expert opinion: KRAS mutation-based cancer vaccines can induce immunogenicity in patients with KRAS-driven cancers. However, the mechanisms of tumor suppression including cellular and molecular factors within the tumor microenvironment may limit vaccine efficacy. Combining KRAS-driven therapeutic cancer vaccines with other methods and adjuvants can circumvent immunosuppression and promote therapeutic successes.


Assuntos
Vacinas Anticâncer/administração & dosagem , Neoplasias/prevenção & controle , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Vacinas Anticâncer/imunologia , Humanos , Imunogenicidade da Vacina , Mutação , Neoplasias/genética , Neoplasias/imunologia , Microambiente Tumoral
16.
Mol Clin Oncol ; 13(1): 38-42, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32499912

RESUMO

Pembrolizumab, an immune checkpoint inhibitor against the programmed death-1 pathway, has been used in combination with acitinib for the first-line treatment of advanced renal cell carcinoma. Neurotoxicity is a rare immune-related adverse event (irAE). The present study reports a case of Guillain-Barre syndrome (GBS) induced by pembrolizumab and sunitinib, and reviews other previous studies to elucidate the clinical characteristics and suitable management of this rare irAE. An advanced renal cell carcinoma patient who received several cycles of pembrolizumab combined with sunitinib developed limb weakness and numbness of the extremities, and was diagnosed with GBS by electrodiagnostic and cerebrospinal fluid examination. The patient improved after treatment with intravenous immunoglobulin along with prednisone. To the best of our knowledge, this is the first case of GBS during treatment with pembrolizumab in combination with sunitinib in advanced renal cell carcinoma.

17.
Transl Cancer Res ; 9(4): 3054-3060, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35117666

RESUMO

Male primary choriocarcinoma is a rare and invasive malignant neoplasm for which traditional chemotherapy has limited efficacy. Pembrolizumab is a humanized monoclonal anti-programmed death-1 antibody that has antitumor activity in numerous malignancies. The diagnosis and treatment of two cases of advanced male primary choriocarcinoma were retrospectively analyzed and relevant literature was reviewed to discuss the prognosis and the efficacy of different treatments, including pembrolizumab. The first patient, who presented with cough and hemoptysis, was diagnosed with primary mediastinal choriocarcinoma. He initially responded to the first-line chemotherapy of etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine, but eventually developed brain metastases. The patient did not respond to the second-line chemotherapy comprising paclitaxel and cisplatin, and he died 6.5 months after diagnosis. The second patient experienced repeated episodes of abdominal pain and was diagnosed with primary neck choriocarcinoma. He received chemotherapy regimens similar to those of the first patient. However, imaging showed no significant changes and his clinical symptoms were not improved. Immunohistochemistry showed that the expression of programmed death ligand 1 on the tumor cells was 40%, and he was administered pembrolizumab combined with chemotherapy. He achieved complete response and was subsequently switched to pembrolizumab maintenance monotherapy. He is still alive without evidence of disease 36 months after diagnosis. To our knowledge, this is the first case of advanced male primary choriocarcinoma successfully treated with pembrolizumab combined with chemotherapy. Advanced male primary choriocarcinoma is highly aggressive and insensitive to chemotherapy. Pembrolizumab may provide a promising treatment option to improve patient outcomes.

18.
Front Oncol ; 10: 608300, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33409155

RESUMO

BACKGROUND: The immune checkpoint inhibitors (ICIs) have achieved great success in the treatment of non-small cell lung cancer (NSCLC) patients. However, the response rate is low. The molecular mechanism involved in the effectiveness of ICIs remains to be elucidated. METHODS: ATRX mutation incidence among human cancers was analyzed from TCGA database. Atrx-deficient Lewis lung cancer cell line (LLC-sgAtrx) was established via AAV-CRISPR. Subcutaneous and metastasis models were established by subcutaneous and intravenous injection of LLC-sgAtrx and LLC-sgNTC cells into female C57BL/6 mice. The mice were treated with anti-PD1, anti-CLTA4 or Rat IgG2a. Tumor volume was determined by Vernier calipers and the IVIS imaging system. The proportions of CD3+ T cells, CD45+ immune cells, and the expression of pMHC I and PDL1 were determined by flow cytometry. The T cell cytotoxicity was determined by co-culture experiment. RESULTS: TCGA data showed that Atrx is a tumor suppressor mutated at high frequency among various human cancers. The tumor volume of mice bearing LLC-sgAtrx was significantly shrinked and the median survival of mice was significantly longer after anti-PD1 and anti-CTLA4 treatment. Flowcytometry results showed that Atrx deficiency increase the penetration of CD3+ T cell into the tumor microenvironment and enhanced antigen presentation after IFNγ stimulation. Additionally, the tumor cells with Atrx deficiency were more easily to be damaged by T cells under IFNγ stimulation. CONCLUSION: The present study demonstrated that Atrx deficiency sensitize lung cancer cells to ICIs by multiple mechanisms. And ATRX may serve as a promising biomarker for ICIs which helps patient stratification and decision making.

19.
Front Oncol ; 10: 575417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363009

RESUMO

INTRODUCTION: Nasopharyngeal carcinoma (NPC) is a common malignancy in China and known prognostic factors are limited. In this study, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI) were evaluated as prognostic factors in locally advanced NPC patients. MATERIALS AND METHODS: NPC patients who received curative radiation or chemoradiation between January 2012 and December 2015 at the Second Xiangya Hospital were retrospectively reviewed, and a total of 516 patients were shortlisted. After propensity score matching (PSM), 417 patients were eventually enrolled. Laboratory and clinical data were collected from the patients' records. Receiver operating characteristic curve analysis was used to determine the optimal cut-off value. Survival curves were analyzed using the Kaplan-Meier method. The Cox proportional hazard model was used to identify prognostic variables. RESULTS: After PSM, all basic characteristics between patients in the high SIRI group and low SIRI group were balanced except for sex (p=0.001) and clinical stage (p=0.036). Univariate analysis showed that NLR (p=0.001), PLR (p=0.008), SII (p=0.001), and SIRI (p<0.001) were prognostic factors for progression-free survival (PFS) and overall survival (OS). However, further multivariate Cox regression analysis showed that only SIRI was an independent predictor of PFS and OS (hazard ratio (HR):2.83; 95% confidence interval (CI): 1.561-5.131; p=0.001, HR: 5.19; 95% CI: 2.588-10.406; p<0.001), respectively. CONCLUSION: Our findings indicate that SIRI might be a promising predictive indicator of locally advanced NPC patients.

20.
Medicine (Baltimore) ; 99(46): e23150, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181687

RESUMO

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) have become the preferred therapy as first-line treatment of non-small cell lung cancer patients harboring sensitizing EGFR mutations. However, the prognostic indicators are limited. The present study aimed to assess the prognostic value of immune-inflammation factors, fibrinogen-albumin ratio index (FARI), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) in EGFR-Mutant lung adenocarcinoma patients receiving first-generation EGFR-TKIs treatment.194 patients were included in this retrospective analysis. FARI was calculated as fibrinogen / albumin. Receiver operating characteristic curve was used to evaluate the optimal cut-off value for FARI, NLR, and PLR to progression free survival (PFS). Univariate and multivariate survival analysis were performed to identify factors correlated with PFS and overall survival (OS).Applying cut-offs of ≥0.08 (FARI), ≥3.28 (NLR), and ≥273.85 (PLR), higher FARI or NLR was associated with worse Eastern Cooperative Oncology Group performance status (ECOG PS) (P = .018, .002, respectively), and there were more males in high NLR group (P = .043). In univariate analysis, ECOG PS status, NLR, PLR, and FARI were significantly associated with PFS (P = .017, .004, <.001, .001, respectively) as well as OS (P < .001, = .001, .002, .023, respectively). In multivariate analysis, PLR (hazard ratios [HR] 1.692; 95% CI 1.054-2.715; P = .029) and FARI (HR 1.496; 95% CI 1.031-2.172; P = .034) were independent prognostic factors for PFS. While only ECOG PS status (HR 2.052; 95% CI 1.272-3.310; P = .003) was independently correlated with OS.FARI is independently associated with PFS in EGFR-Mutant lung adenocarcinoma patients receiving first-line EGFR-TKIs treatment.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB/genética , Fibrinogênio/análise , Inibidores de Proteínas Quinases/uso terapêutico , Albumina Sérica Humana/análise , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores/sangue , Contagem de Células Sanguíneas/métodos , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão
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