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Receptor-interacting protein kinase 4 (RIPK4) is increasingly recognized as a pivotal player in ovarian cancer, promoting tumorigenesis and disease progression. Despite its significance, the posttranslational modifications dictating RIPK4 stability in ovarian cancer remain largely uncharted. In this study, we first established that RIPK4 levels are markedly higher in metastatic than in primary ovarian cancer tissues through single-cell sequencing. Subsequently, we identified UCHL3 as a key deubiquitinase that regulates RIPK4. We elucidate the mechanism that UCHL3 interacts with and deubiquitinates RIPK4 at the K469 site, removing the K48-linked ubiquitin chain and thus enhancing RIPK4 stabilization. Intriguingly, inhibition of UCHL3 activity using TCID leads to increased RIPK4 ubiquitination and degradation. Furthermore, we discovered that GSK3ß-mediated phosphorylation of RIPK4 at Ser420 enhances its interaction with UCHL3, facilitating further deubiquitination and stabilization. Functionally, RIPK4 was found to drive the proliferation and metastasis of ovarian cancer in a UCHL3-dependent manner both in vitro and in vivo. Importantly, positive correlations between RIPK4 and UCHL3 protein expression levels were observed, with both serving as indicators of poor prognosis in ovarian cancer patients. Overall, this study uncovers a novel pathway wherein GSK3ß-induced phosphorylation of RIPK4 strengthens its interaction with UCHL3, leading to increased deubiquitination and stabilization of RIPK4, thereby promoting ovarian cancer metastasis. These findings offer new insights into the molecular underpinnings of ovarian cancer and highlight potential therapeutic targets for enhancing antitumor efficacy.
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Glucógeno Sintasa Quinasa 3 beta , Neoplasias Ováricas , Ubiquitina Tiolesterasa , Ubiquitinación , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/genética , Femenino , Humanos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Animales , Ratones , Línea Celular Tumoral , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Metástasis de la Neoplasia , Homeostasis , Fosforilación , Proliferación Celular/genética , Ratones DesnudosRESUMEN
Polycystic ovary syndrome (PCOS) is a multifactorial disease, which is closely related to obesity. This study evaluated the efficacy of bariatric surgery on obesity complicated with PCOS through meta-analysis. PubMed, Cochrane, EMbase, and WOS databases were searched from 2012 to November 2022. Studies on the efficacy of bariatric surgery in the treatment of obesity combined with PCOS were included. Outcome indicators included menstrual abnormalities, BMI, free testosterone, hypertrichosis, and ovarian volume. Methodological quality of the included studies was evaluated, and statistical analysis was performed using RevMan 5.3 software. Finally, 9 studies were included, and the results of meta-analysis were as follows: After weight loss surgery, menstrual irregularity decreased (RR = -0.83, 95%CI:-1.00â¼-0.65, P < 0.00001), and BMI decreased significantly (MD = -13.64, 95%CI:-16.29â¼-10.99, P < 0.00001). Free testosterone levels decreased (MD = -22.70, 95 % CI: -36.07 â¼ -9.34, P < 0.00001), the incidence of hypertrichosis decreased (RR = 0.63, 95%CI: 0.45-0.88, p = 0.007 < 0.01), and the ovarian volume decreased (MD = -3.09, 5%CI: -5.76 â¼ -0.42, P < 0.00001).
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Transumbilical single-port laparoscopy is widely used in gynecological surgery. However, it is rarely used in the treatment of deep infiltrating endometriosis due to its own shortcomings and the complex condition of deep infiltrating endometriosis. The study aims to introduce a transumbilical single-port laparoscopic surgery based on retroperitoneal pelvic spaces anatomy, which can complete the operation of deep infiltrating endometriosis more easily. A retrospective analysis of 63 patients with deep infiltrating endometriosis treated by transumbilical single-port laparoscopy using this method was conducted. The operation duration was 120.00 (85.00 ± 170.00) (35-405) min, the estimated blood loss was 68.41 ± 39.35 ml, the postoperative hospital stay was 5.00 (4.00-6.00) days, and the incidence of postoperative complications was 4.76% (3/63). 1 patient was found to have intestinal injury during operation, 1 patient had ureteral injury after operation, and 1 patient had postoperative pelvic infection, with a recurrence rate of 9.52%. The postoperative scar score was 3.00 (3.00-4.00) and the postoperative satisfaction score was 9.00 (8.00-10.00). In summary, this study demonstrates the feasibility of transumbilical single-port laparoscopic surgery for deep infiltrating endometriosis based on retroperitoneal pelvic spaces anatomy. Hysterectomy, adenomyosis resection, etc. are also feasible with this method, boasting more obvious advantages. This method can make transumbilical single-port laparoscopy more widely used in deep infiltrating endometriosis.
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Endometriosis , Laparoscopía , Femenino , Humanos , Estudios Retrospectivos , Endometriosis/cirugía , Endometriosis/etiología , Laparoscopía/efectos adversos , Laparoscopía/métodos , Pelvis/cirugía , Histerectomía/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugíaRESUMEN
Currently, for ovarian cancer, which has the highest mortality rate among all gynecological cancers, the standard treatment protocol is initial tumor cytoreductive surgery followed by platinum-based combination chemotherapy. Although the survival rate after standard treatment has improved, the therapeutic effect of traditional chemotherapy is very limited due to problems such as resistance to platinum-based drugs and recurrence. With the advent of the precision medicine era, molecular targeted therapy has gradually entered clinicians' view, and individualized precision therapy has been realized, surpassing the limitations of traditional therapy. The detection of genetic mutations affecting treatment, especially breast cancer susceptibility gene (BRCA) mutations and mutations of other homologous recombination repair defect (HRD) genes, can guide the targeted drug treatment of patients, effectively improve the treatment effect and achieve a better patient prognosis. This article reviews different sites and pathways of targeted therapy, including angiogenesis, cell cycle and DNA repair, and immune and metabolic pathways, and the latest research progress from preclinical and clinical trials related to ovarian cancer therapy.
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Treatment of cetuximab-resistant colorectal cancer (CRC) is a global healthcare problem. This study aimed to assess the effects of radiotherapy on cetuximab-resistant CRC and explore the underlying mechanism. We established a cetuximab-resistant HCT116 cell line (HCT116-R) by extracorporeal shock. Differentially expressed mRNAs were screened from cells treated with different radiation doses using second-generation high-throughput sequencing. Sequence data showed that ACY1 was significantly downregulated in HCT116-R cells after irradiation. Analysis of the GEO and TCGA datasets revealed that high ACY1 expression was associated with lymph node metastasis and a poor prognosis in CRC patients. In addition, immunohistochemistry results from CRC patients revealed that ACY1 protein expression was related to cetuximab resistance and lymph node metastasis. These findings suggested that ACY1 may function as an oncogene to promote CRC progression and regulate the radiosensitivity of cetuximab-resistant CRC. As expected, ACY1 silencing weakened the proliferation, migration, and invasion abilities of HCT116-R cells after radiotherapy. Mechanistically, TCGA data demonstrated that ACY1 expression was closely related to the Wnt/ß-catenin pathway in CRC. We validated that radiotherapy first reduced ß-catenin levels, followed by decreased expression of the metastasis-related protein E-cadherin. Silencing ACY1 dramatically enhanced these changes in ß-catenin and E-cadherin after radiotherapy. In conclusion, ACY1 downregulation could enhance the radiosensitivity of cetuximab-resistant CRC by inactivating Wnt/ß-catenin signaling, implying that ACY1 may serve as a radiotherapy target for cetuximab-resistant CRC.
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Acinetobacter baumannii (A. baumannii) is an opportunistic pathogen and leading cause of health care-associated infections. Several known pathogenic factors, including lipopolysaccharide, capsular polysaccharides, phospholipase, protein secretion systems, two component efflux pumps and biofilm formation, are associated with the bacteria. However, owing to the new biological characteristics rapidly developed under the external stress, the pathogenesis becomes complicated. The formation of mucoid phenotype is a major adaptive defense response for A. baumannii. The mucus is mainly comprised of capsular polysaccharide, which forms a barrier around the bacterial cell wall, and provides protection from environmental pressures and host immune responses. Importantly, mucoid formation has been shown to confer changes in the pathogenicity and pathogenesis of A. baumannii. Thus, this review aims to highlight the biological characteristics, virulence and underlying pathogenic mechanisms of mucoid A. baumannii. We primarily provide profound insight into the structure, function and detecting methods of the mucus in mucoid A. baumannii. Then we mainly illustrate the current studies on mucoid A. baumannii. Finally, the unsolved areas associated with mucoid A. baumannii are summarized. In summary, this review will critically offer a comprehensive understanding of mucoid A. baumannii and provide novel insight into the diagnosis and intervention strategies for the increasingly deadly human pathogen.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Infección Hospitalaria , Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/genética , Biopelículas , Infección Hospitalaria/microbiología , Farmacorresistencia Bacteriana Múltiple/genética , Humanos , Virulencia/genéticaRESUMEN
Resistance to first-line chemotherapy drugs has become an obstacle to improving the clinical prognosis of patients with small cell lung cancer (SCLC). Exosomal microRNAs have been shown to play pro- and anti-chemoresistant roles in various cancers, but their role in SCLC chemoresistance has never been explored. In this study, we observed that the expression of exosomal miR-92b-3p was significantly increased in patients who developed chemoresistance. Luciferase reporter analysis confirmed that PTEN was a target gene of miR-92b-3p. The PTEN/AKT regulatory network was related to miR-92b-3p-mediated cell migration and chemoresistance in vitro and in vivo in SCLC. Importantly, exosomes isolated from the conditioned medium of SBC-3 cells overexpressing miR-92b-3p could promote SCLC chemoresistance and cell migration. Furthermore, we found that plasma miR-92b-3p levels were significantly higher in patients with chemoresistant SCLC than in those with chemosensitive SCLC, but the levels were down-regulated in patients who achieved remission. Kaplan-Meier analysis showed that SCLC patients with high miR-92b-3p expression were associated with shorter progression-free survival. Overall, our results suggested that exosomal miR-92b-3p is a potential dynamic biomarker to monitor chemoresistance in SCLC and represents a promising therapeutic target for chemoresistant SCLC.
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Mucoid phenotype is an important adaptive defense response for Acinetobacter baumannii (A. baumannii). The aim of this study was to analyze the impact of mucoid phenotype for the molecular characteristics and virulence of A. baumannii. We observed that the colonies of mucoid A. baumannii were moist, with an elevated surface, and the wire drawing result was positive. Transmission electron microscopy data showed that the outer wall of the mucoid colonies was not smooth, had protruding pseudopodia, and was surrounded by a layer of unknown material. Antibiotic susceptibility testing showed that the mucoid strains were multidrug resistant. Notably, the mucoid phenotype and antibiotic resistance were not correlated with the amount of biofilm produced by A. baumannii. MLST data demonstrated that the mucoid A. baumannii strains belonged to type ST2. Most (82.6 %, 38/46) of the multidrug-resistant nonmucoid strains also belonged to the molecular type ST2 and to other types, including ST129, ST158, ST195, ST80 and ST3. Moreover, mucoid A. baumannii strains were more virulent than nonmucoid isolates in a mouse model. The comparative transcriptomic data indicated that 15 genes, especially IX87_RS16955 (acnA), IX87_RS10800 (XanP), IX87_RS12875 (GlmM), IX87_RS00885 and IX87_RS12395 (bfr), were possibly associated with the phenotype and virulence of mucoid A. baumannii. In conclusions, the study comprehensively describes the molecular characteristics and virulence regulatory mechanism of mucoid A. baumannii, and provides novel insights for the prevention and treatment of infections associated with these strains.
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Acinetobacter baumannii/genética , Acinetobacter baumannii/patogenicidad , Antibacterianos/farmacología , Factores de Virulencia/genética , Virulencia , Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/ultraestructura , Animales , Biopelículas/crecimiento & desarrollo , Farmacorresistencia Bacteriana Múltiple , Femenino , Perfilación de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Tipificación de Secuencias Multilocus , FenotipoRESUMEN
OBJECTIVE: Lung cancer screening with low-dose computed tomography (LDCT) partly reduces cancer-specific mortality. However, few data have described this specific population for screening in mainland China. Here, we conducted a population-based screening program in Anhui, China. METHODS: 9084 individuals were participating in the screening program for lung cancer in Anhui province from 1 June 2014 to 31 May 2017. LDCT was offered to all participants who joined the program. RESULTS: Of 9084 individuals undergoing LDCT, we detected 54 lung cancers (0.594%). The age with the highest rate was 61-65 years (up to 1.016%), followed by 56-60 (0.784%). Most patients (98.1%, 53/54) were in stage I-II (early stage), and only one was in stage III (advanced stage). Adenocarcinoma, squamous cell carcinoma and small cell lung cancer accounted for 57.4% (31/54), 37% (20/54) and 5.6% (3/54) of the individuals, respectively. Notably, There were 4,102 never smokers in our study. The median age was 63 years. Males and females accounted for 53.4 and 46.6%, respectively. Among the 4102 never smokers, 96 participants had a positive family cancer history. Additionally, we detected 20 lung cancers (0.488%), slightly lower than the whole rate 0.594%. Finally, our data showed that age, smoking, family cancer history and features of nodules were risk factors for lung cancer. CONCLUSION: Our study qualified the efficiency of LDCT to detect early-stage lung cancers in Anhui, China. Further establishment of appropriate lung cancer screening methods specifically for individuals in China is warranted. ADVANCES IN KNOWLEDGE: We evaluated the performance of lung cancer screening for asymptomatic populations using LDCT in Anhui, an eastern inland province of China. Our study qualified the efficiency of LDCT to detect early-stage lung cancers in Anhui, China.
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Neoplasias Pulmonares/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adulto , Factores de Edad , Anciano , China , Femenino , Humanos , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Dosis de Radiación , Centros de Atención TerciariaRESUMEN
miRNAs have been reported to be stably detectable in plasma and to function as potent biomarkers in multiple cancers. The study aimed to evaluate the expression of candidate circulating miRNAs in patients with small cell lung cancer (SCLC) to identify potential noninvasive biomarkers. The expression of five miRNAs (miR-92b, miR-146a, miR-375, miR-1224, and miR-1246) was significantly upregulated in plasma after chemoresistance induction. Receiver operating characteristic curve (ROC) analysis showed that the area under the curve (AUC) values of miR-92b and miR-375 were 0.766 and 0.791, respectively. The data demonstrated that among the five miRNAs assessed, these two miRNAs had better diagnostic accuracy for monitoring drug resistance. In addition, miR-92b and miR-375 levels were decreased after effective chemotherapy. Furthermore, Kaplan-Meier survival analysis confirmed that high expression of miR-92b and miR-375 was closely related to shorter progression-free survival (PFS) in SCLC patients. In conclusion, these findings indicate that circulating miR-92b and miR-375 might be ideal noninvasive biomarkers for monitoring drug resistance during chemotherapy and evaluating the prognosis of patients with SCLC.
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Resistencia a Antineoplásicos , Neoplasias Pulmonares/genética , MicroARNs/sangre , Carcinoma Pulmonar de Células Pequeñas/genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Análisis de SupervivenciaRESUMEN
BACKGROUND: Invasive Gram-positive bacilli infections are commonly encountered in immunocompromised patients. In this paper, we report a bacteremia caused by Turicella otitidis in a patient with diffuse large B-cell lymphoma. METHODS: Bacteria was identified by VITEK MALDI-TOF MS. Drug sensitivity was analyzed by disk diffusion method. RESULTS: MALDI-TOF MS data demonstrated that the infection bacteria was Turicella otitidis. Drug susceptibility data showed that Turicella otitidis was possibly sensitive to vancomycin, polymyxin B, and chloramphenicol. Body temperature of the patient dropped after administration of vancomycin. The data indicated that vancomycin could be used to treat the infections caused by Turicella otitidis. CONCLUSIONS: MALDI-TOF MS can be used for the rapid and accurate identification of Turicella otitidis. Vancomycin can be used to treat the infection caused by Turicella otitidis. This study may provide a reference for the diagnosis and treatment of Turicella otitidis.
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Bacteriemia , Infecciones por Corynebacterium , Corynebacterium , Linfoma de Células B Grandes Difuso/complicaciones , Anciano , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacteriemia/complicaciones , Bacteriemia/microbiología , Infecciones por Corynebacterium/complicaciones , Infecciones por Corynebacterium/microbiología , Femenino , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Invasive fungal infections often occur in immunocompromised patients. Here, we report an infection case caused by Geotrichum capitatum in a severe aplastic anemia patient. METHODS: Identification of the pathogenic bacteria was done by sequencing and mass spectrometric analysis. RESULTS: The fungal infection was isolated from blood cultures. The pathogenic bacteria were identified as Geotrichum capitatum. The infection was primarily cured by voriconazole and caspofungin monotherapy. However, the effect was not obvious. Then a combination of liposomal amphotericin B and caspofungin was used. Body temperature of the patient decreased, and clinical symptoms improved. CONCLUSIONS: Sequencing and mass spectrometric analysis could have a role for Geotrichum capitatum diagnosis. Curative effect of using a single antifungal drug was unsatisfactory. Using liposome amphotericin B combined with caspofungin might obtain certain curative effect. Early diagnosis and appropriate combined therapy were necessary to improve the outcome of patients with Geotrichum capitatum infection.
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Anemia Aplásica/complicaciones , Geotrichum/efectos de los fármacos , Micosis/tratamiento farmacológico , Adolescente , Anfotericina B/uso terapéutico , Anemia Aplásica/patología , Antifúngicos/uso terapéutico , Caspofungina/uso terapéutico , Quimioterapia Combinada , Femenino , Geotrichum/fisiología , Humanos , Micosis/complicaciones , Micosis/microbiología , Índice de Severidad de la Enfermedad , Voriconazol/uso terapéuticoRESUMEN
Epidermal growth factor receptor (EGFR) mutations are more common in non-small cell lung cancer (NSCLC) and in female patients of East Asian origin. Therefore, the present study investigated the presence of EGFR mutations in advanced NSCLC, and assessed its correlation with clinicopathologic factors, including the expression of estrogen receptor-ß (ER-ß) and patient prognosis. The present study performed a retrospective analysis of 83 patients with stage IIIB-IV NSCLC. The expression of ER-ß and p53 were examined using immunohistochemical methods. EGFR mutations were evaluated using the amplification refractory mutation system. The expression of ER-ß and p53 were detected in 37 (45.6%) and 48 (57.8%) of the patient tumors, respectively. EGFR mutations were identified in 36 (45.4%) cases. EGFR mutations were more frequently observed in ER-ß-negative tumors (26/46; 56.5%), compared with ER-ß-positive tumors (10/37; 27%). The expression of ER-ß was significantly associated with EGFR mutations with an odds ratio (OR) of 0.241 (P=0.029). However, no significant correlation was observed between the expression of p53 and mutations in EGFR (OR=1.792; P=0.340). In addition, the expression of ER-ß and lymph node metastasis were associated with poor prognosis, whereas EGFR mutations were significantly associated with favorable prognosis in terms of progression-free survival rates. However, there was no prognostic significance associated with the expression of p53. In conclusion, the expression of ER-ß was significantly correlated with the presence of EGFR mutations. The expression of ER-ß and mutations of EGFR were found to be prognostic factors for survival rates in patients with advanced NSCLC.
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Although the studies on the pathogenesis and prognosis of leukemia have made revolutionary progress, the long-term survival remains unsatisfactory. Alternative techniques are being developed to target leukemia. Several decades after researchers' work, a variety of bacteria toxins are being explored as potential anti-leukemia agents, either to provide direct effects or to deliver therapeutic proteins to leukemia. LukS-PV, a component of Panton-Valentine Leukocidin secreted by S. aureus, has been tested in acute myeloid leukemia as a novel experimental strategy. Further researches about the targeting mechanisms of LukS-PV are required to make it a complete therapeutic approach for leukemia treatment. The function of this article is to provide clinicians and experimentalists with a chronological and comprehensive appraisal of use of LukS-PV as an experimental strategy for leukemia therapy.
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Antineoplásicos/uso terapéutico , Proteínas Bacterianas/uso terapéutico , Toxinas Bacterianas/uso terapéutico , Exotoxinas/uso terapéutico , Leucemia/tratamiento farmacológico , Leucocidinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Toxinas Bacterianas/administración & dosificación , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Estabilidad de Medicamentos , Exotoxinas/administración & dosificación , Humanos , Leucemia/patología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucocidinas/administración & dosificación , Terapias en Investigación/tendenciasRESUMEN
Human papilloma virus (HPV) infection has previously been reported to be associated with TP53 and TP16 expression in Japanese and Taiwanese patients with lung cancer, but data for advanced non-small cell lung cancer (NSCLC) patients is limited. The present study examined the association between HPV infection and TP53 and TP16 expression in Chinese patients with advanced NSCLC. HPV DNA was detected in 20 out of 83 (24%) lung tumors, and was observed more frequently in non-smokers, patients with lymph node metastasis, and patients with poorly differentiated tumors (P=0.048, P=0.044 and P=0.024, respectively). Thirteen (65%) out of 20 HPV-infected tumors were positive for TP53 expression while eight (40%) were positive for TP16 expression. Multivariate analysis revealed that poor differentiation alone (OR=0.163) was an independent predictive factor of HPV infection in NSCLC. TP16-positive patients had a significantly longer survival time when compared with TP16-negative patients (P<0.001, log-rank test), a trend a not observed for TP53. Our results suggest that TP53 and TP16 protein expression is not associated with the expression of HPV DNA, but that TP16 expression may be an independent prognostic factor of long survival in advanced NSCLC.
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Previous studies have demonstrated an association between human papillomavirus (HPV) and mutations in the epidermal growth factor receptor (EGFR) gene in lung cancer patients; however, few studies have investigated this association in advanced lung adenocarcinoma patients undergoing gefitinib treatment. The present study investigated the association between HPV and EGFR mutations in advanced lung adenocarcinoma patients. A total of 95 advanced lung adenocarcinoma patients were enrolled in the study. The HPV infection status and presence of EGFR mutations in tumor tissue was evaluated. Patient clinical characteristics were also determined and compared with HPV infection and EGFR mutation status to analyze their impact on progression-free survival. HPV DNA was identified in 27/95 (28.4%) lung adenocarcinoma tumors and was most common in patients with lymph node metastasis (P=0.016). A total of 44/95 (46.3%) cases exhibited EGFR mutations, which were predominantly observed in female patients and non-smokers. The presence of HPV DNA was significantly associated with EGFR mutations (P=0.012) and multivariate analysis also revealed that HPV DNA was significantly associated with EGFR mutations (odds ratio=3.971) in advanced lung adenocarcinoma. Patients with both HPV infections and EGFR mutations exhibit a marked decrease in the risk of lung cancer progression when compared with those without HPV infection or EGFR mutations (adjusted HR=0.640; 95% confidence interval: 0.488-0.840; P=0.001). HPV infection was significantly associated with EGFR mutations in advanced lung adenocarcinoma patients. Furthermore, patients with HPV infections exhibited the longest progression-free survival times, which may be due to good response to tyrosine kinase inhibitor- or platinum-based-adjuvant therapy in these patients. Patients with EGFR mutations exhibited a better prognosis when compared with those exhibiting wild-type EGFR, regardless of HPV status.
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MicroRNAs have become recognized as key players in the development of malignancy. MiR-200c can function as a tumor suppressor gene. However, the effect of miR-200c on methotrexate resistance remains unclear to date. This study aims to evaluate the function of miR-200c in lung cancer A549 cells. The data presented in our study demonstrated that the expression of miR-200c was down-regulated in methotrexate-resistant A549 cells. Over expression of miR-200c could significantly inhibit cell proliferation, induce G0/G1 cell cycle arrest and induce cell apoptosis. RT-PCR and Western blot assays showed that the expression of P53 and P21 were significantly increased with miR-200c overexpression. These results indicated that over expression of miR-200c might enhance the sensitivity of A549 cells to methotrexate through the P53/P21 pathway. Furthermore, miR-200c overexpression significantly inhibited cell migration and invasion with increasing the expression of E-cad and decreasing the expression of EZH2. In consequence, we provide a mechanism of acquired resistance to methotrexate that is caused by the loss of miR-200c in lung cancer cells. Along with this, our study demonstrates the complex network of microRNA mediated chemoresistance.
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Antimetabolitos Antineoplásicos/farmacología , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/metabolismo , Metotrexato/farmacología , MicroARNs/genética , Apoptosis/efectos de los fármacos , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Humanos , Neoplasias Pulmonares/genética , MicroARNs/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
LukS-PV, a component of Panton-Valentine leukocidin (PVL) secreted by Staphylococcus aureus, has been shown to inhibit proliferation and induce apoptosis in acute myeloid leukemia (AML) THP-1 cells. Here we investigated anti-leukemia activities of LukS-PV in HL-60 cells, using in vitro assays to assess the ability of LukS-PV to mediate cell viability, apoptosis and differentiation; and developing a Severe Combined Immunodeficiency (SCID) mouse model of disseminated AML with the HL-60 cells to examine in vivo anti-leukemia activity. LukS-PV inhibited viability and induced differentiation and apoptosis in the HL-60 AML cell line. In the SCID mice, LukS-PV potently inhibited tumor growth, decreased tumor cell infiltration into peripheral blood and tissues, and significantly increased mean survival time. No severe adverse effects, such as death, weight loss, or pathological changes in livers or spleens were observed in the toxicity test group. These results indicate that LukS-PV may be a novel and effective chemotherapeutic agent against AML.
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Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/farmacología , Exotoxinas/metabolismo , Exotoxinas/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucocidinas/metabolismo , Leucocidinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células HL-60 , Humanos , Técnicas In Vitro , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Ratones SCID , Subunidades de Proteína , Distribución Aleatoria , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The discovery of the immunodeficient mice has provided a tool for establishing animal models as hosts for in vivo analysis of AML. Various model systems have been established in the last few decades, and it is essential that murine AML models are developed to exploit more specific, targeted therapeutics. In this review, we concentrate on the models of AML and discuss the development of immunodeficiency models for understanding of leukemogenesis, describe those now available and their values and document the methods used for establishing and identifying AML mice models, as well as factors influencing engraftment of human AML in immunodeficient mice. Thus, the function of this article is to provide clinicians and experimentalists with a chronological, comprehensive appraisal of all AML model systems.
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Modelos Animales de Enfermedad , Leucemia Mieloide Aguda/genética , Animales , Ingeniería Genética , Humanos , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Ratones , Ratones SCID , Trasplante de Neoplasias , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Staphylococcus aureus (S. aureus) is a major nosocomial pathogen that causes a variety of infections and toxicoses. In recent years, the percentage of rifampicin-resistant S. aureus has increased rapidly in China. The aims of this study were to analyze 1) the level of rifampicin resistance in S. aureus and its correlation with mutations in the rpoB gene, and 2) the molecular characterization of rifampicin-resistant S. aureus isolates. RESULTS: 88 rifampicin-resistant S. aureus isolates were collected for this study. Of the 88 isolates, 83 (94.3%) were high-level rifampicin resistant (MIC≥8 mg/L) while the remaining 5 isolates (5.7%) had a low-level resistance to rifampicin (MIC, 2 to 4 mg/L). Four amino acid substitutions were found in the 88 isolates, which were 481His/Asn (95.5%), 466Leu/Ser (87.5%), 477Ala/Asp (6.8%) and 486Ser/Leu (4.5%) respectively. All mutations were found to be present in cluster I of the rpoB gene. The low-level resistant isolates were found to have only one mutation, while the high-level resistant isolates had at least two or more mutations. The most common multiple mutations were 481His/Asn+466Leu/Ser(92.8%,77/83). The other multiple mutations found were 481His/Asn+477Ala/Asp (6.0%,5/83), and 481His/Asn+466Leu/Ser+477Ala/Asp (1.2%,1/83). Out of 28 high-level rifampicin-resistant S. aureus isolates, three molecular types were found, namely, ST239-MRSA-III-spa t030 (25/28, 89.3%), ST239-MRSA-III-spa t021 (2/28, 7.1%), and ST239-MRSA-III-spa t045 (1/28, 3.6%). CONCLUSIONS: Rifampicin resistance in S. aureus was closely associated with mutations in the rpoB gene. High-level rifampicin-resistant S. aureus is one of the most important features in Anhui Provincial Hospital, and high-level rifampicin resistance in S. aureus is associated with multiple mutations of rpoB gene. The prevalence of high-level rifampicin-resistant S. aureus in Anhui may be associated with the spread of the ST239-MRSA III-spa t030 clone.