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BACKGROUND: Although the phosphorylation of 4E-BP1 that has been detected in high-grade prostate cancer has been reported in previous studies, overexpression of p4E-BP1 and 4EBP1 and their clinical significance in prostate cancer still remain unknown. METHODS: One hundred six samples of prostate tissues were collected and analyzed by immunohistochemistry with p4E-BP1 or 4E-BP1 specific antibodies. Everolimus was used to block the phosphorylation of p4E-BP1, and then flow cytometry, clone formation, transwell, and wound healing assays were performed to detect the survival and invasive ability of the prostate cancer cells. RESULTS: We found that the expression of 4E-BP1 and p4E-BP1 was higher in prostate cancer tissues than in normal tissues. Interestingly, the expression of p4E-BP1 was significantly associated with Gleason score and lymph node metastasis, but had no obvious correlation with PSA and the presence of bone or visceral metastasis. However, no evident correlation was found between the positive expression of 4E-BP1 and these clinical characteristics. In in vitro experiments, we found similar results as the clinical presentation that 4E-BP1 and p4E-BP1 were low expressed in normal prostate epithelial cells, but in prostate cancer cells, as the malignancy increasing, 4E-BP1 and p4E-BP1 expression also gradually increased. Then, we used Everolimus to inhibit the phosphorylation of 4E-BP1 and found that Everolimus effectively reduced cloning formation, inhibited cell migration, and promoted apoptosis in a dose-dependent manner in PC3 cells. CONCLUSIONS: These findings suggest that p4E-BP1 is a potential biomarker and therapy target for prostate cancer, and patients with high expressions of p4E-BP1 may benefit from Everolimus treatment.
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Everolimus , Neoplasias de la Próstata , Everolimus/farmacología , Humanos , Inmunohistoquímica , Masculino , Fosfoproteínas , FosforilaciónRESUMEN
Background: The predominant feature of cancer cells during the process of carcinogenesis is the inclination towards glycolytic metabolism rather than mitochondrial oxidative phosphorylation. Nevertheless, there is a scarcity of research investigating the correlation between bladder cancer and mitochondrial energy metabolism. Methods: A qPCR array comprising 90 genes associated with mitochondrial oxidative phosphorylation was employed to discern metabolic disparities between three sets of bladder cancer tissue and adjacent normal tissue. Wound healing and transwell assays were utilized to assess cell migration and invasion capabilities, respectively. Colony formation assays were conducted to ascertain the tumorigenic potential of the cells. The proliferative capacity of the cells was examined through in vitro CCK-8 assays. Additionally, nude mouse models were established to evaluate the impact of bladder tumor cells on in vivo proliferation. The Seahorse XFe96 Analyzer was utilized to quantify mitochondrial oxidative phosphorylation, while the levels of glucose-6-phosphate and pyruvate were assessed to evaluate glycolysis. Results: Examination of qPCR array data demonstrated a noteworthy inhibition of mitochondrial oxidative phosphorylation in bladder cancer tissue, as evidenced by the down-regulation of a majority of genes associated with mitochondrial energy metabolism. Notably, GADD45B may potentially exert a significant influence on bladder cancer development, warranting further investigation. The down-regulation of GADD45B in bladder cancer cells resulted in impaired mitochondrial respiration and elevated levels of glycolysis, thereby enhancing cell migration and invasion. Conversely, up-regulation of GADD45B had the opposite effect. Furthermore, over-expression of GADD45B inhibited tumor proliferation and tumorigenesis in both in vitro and in vivo settings. Conclusion: These findings from our study indicate that the down-regulation of GADD45B promotes the shift of cell mitochondrial oxidative phosphorylation towards glycolysis, thereby facilitating the progression of bladder cancer.
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Neuroendocrine prostate cancer (NEPC) is a highly aggressive variant of castration-resistant prostate cancer. It is characterized by low or no expression of the androgen receptor (AR), activation of AR-independent signaling, and increased neuroendocrine phenotype. Most of NEPC is induced by treatment of androgen deprivation therapy and androgen receptor pathway inhibitors (ARPIs). Currently, the treatment of NEPC follows the treatment strategy for small-cell lung cancer, lacking effective drugs and specific treatment options. This review summarizes potential novel targets and therapies for NEPC treatment, including epigenetic regulators (zeste homolog 2 inhibitors, lysine-specific demethylase 1 inhibitors), aurora kinase A inhibitors, poly-ADP-ribose polymerase inhibitors, delta-like ligand 3 targeted therapies, a combination of immunotherapies, etc. Other promising targets and future directions are also discussed in this review. These novel targets and therapies may provide new opportunities for the treatment of NEPC.
This review summarizes potential novel targets and therapies for NEPC treatment, including epigenetic regulators (EZH2 inhibitors, LSD-1 inhibitors), AURKA inhibitors, PARP inhibitors, and DLL3 targeted therapies, and combination of immunotherapies, etc. These novel targets and therapies may provide new opportunities in the treatment of NEPC.
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Sinularin, a natural product that purified from soft coral, exhibits anti-tumor effects against various human cancers. However, the mechanisms are not well understood. In this study, we demonstrated that Sinularin inhibited the viability of human prostate cancer cells in a dose-dependent manner and displayed significant cytotoxicity only at high concentration against normal prostate epithelial cell RWPE-1. Flow cytometry assay demonstrated that Sinularin induced tumor cell apoptosis. Further investigations revealed that Sinularin exerted anti-tumor activity through intrinsic apoptotic pathway along with up-regulation of pro-apoptotic protein Bax and PUMA, inhibition of anti-apoptotic protein Bcl-2, mitochondrial membrane potential collapses, and release of mitochondrial proteins. Furthermore, we illustrated that Sinularin induced cell apoptosis via up-regulating PUMA through inhibition of FOXO3 degradation by the ubiquitin-proteasome pathway. To explore how Sinularin suppress FOXO3 ubiquitin-proteasome degradation, we tested two important protein kinases AKT and ERK that regulate FOXO3 stabilization. The results revealed that Sinularin stabilized and up-regulated FOXO3 via inhibition of AKT- and ERK1/2-mediated FOXO3 phosphorylation and subsequent ubiquitin-proteasome degradation. Our findings illustrated the potential mechanisms by which Sinularin induced cell apoptosis and Sinularin may be applied as a therapeutic agent for human prostate cancer.
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Proteínas Reguladoras de la Apoptosis , Diterpenos , Compuestos Heterocíclicos con 3 Anillos , Neoplasias de la Próstata , Humanos , Masculino , Apoptosis , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Proteína Forkhead Box O3 , Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Complejo de la Endopetidasa Proteasomal , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ubiquitinas/metabolismoRESUMEN
OBJECTIVE: To explore clinical effects of the stageâ repair of full-thickness skin defect at dorsal skin of middle phalanx fingers using artificial dermis combing with digital artery perforator fascial flaps. METHODS: From January 2019 to May 2020, 21 patients(27 middle phalanx fingers)with full-thickness skin defect were repaired at stageâ using artificial dermis combing with digital artery perforator fascial flaps. All patients were emergency cases, and were accompanied by the exposure of bone tendon and the defects of periosteum and tendon membrane. Among patients, including 11 males and 10 females aged from 18 to 66 years old with an average age of (39.00±8.01) years old;9 index fingers, 10 middle fingers and 8 ring fingers;range of skin defect area ranged from (2.5 to 3.5) cm×(1.5 to 3.0) cm;range of exposed bone tendon area was (1.5 to 2.0) cm×(1.0 to 2.0) cm. The time from admission to hospital ranged from 1 to 6 h, operation time started from 3 to 8 h after injury. RESULTS: All patients were followed up from 6 to12 months with an average of (9.66±1.05) months. The wounds in 26 cases were completely healed at 4 to 6 weeks after operation. One finger has changed into wound infection with incompletely epithelialized dermis, and achieved wound healing at 8 weeks after dressing change. All fingers were plump with less scars. The healed wound surface was similar to the color and texture of the surrounding skin. These fingers have excellent wearability and flexibility. According to the upper limb function trial evaluation standard of Hand Surgery Society of Chinese Medical Association, the total score ranged from 72 to 100. 26 fingers got excellent result and 1 good. CONCLUSION: Stageâ repair of full-thickness skin defect at dorsal skin of middle phalanx fingers using artificial dermis combing with digital artery perforator fascial flaps is easy to operate with less trauma. It has made satisfactory recovery of appearance and function of fingers. It could provide an effective surgical method for clinical treatment of full-thickness skin loss of fingers with tendon and bone exposure.
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Dedos , Colgajo Perforante , Femenino , Masculino , Humanos , Adulto , Persona de Mediana Edad , Adolescente , Adulto Joven , Anciano , Piel , Arteria Cubital , DermisRESUMEN
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combined with sensitizer is a potential method to reverse TRAIL-resistance in tumor cells. Rhein (RH) is a monomer extracted from Chinese herbs that has been reported to show anti-tumor effects in a variety of tumor cells, but the role of RH in TRAIL-induced anti-tumor effects in bladder cancer cells has not been reported. In this study, we found that the combined treatment of a non-toxic concentration of RH with TRAIL significantly inhibited the proliferation and induced apoptosis in both TRAIL sensitive and resistant bladder cancer cell lines. Furthermore, we found that RH promoted bladder cancer cell apoptosis by up-regulating DR5 expression. Our findings provide potential value in the clinical treatment of bladder cancer.
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Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Neoplasias de la Vejiga Urinaria , Antraquinonas , Apoptosis , Línea Celular Tumoral , Humanos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Renal cell carcinoma (RCC) is a tumor with unpredictable presentation and poor clinical outcome. RCC is always resistant to chemotherapy and radiation, and weakly sensitive to immunotherapeutic agents. Therefore, novel agents and approaches are urgently needed for the treatment of RCC. Emodin, an anthraquinone compound extracted from rhubarb and other traditional Chinese herbs, has been implicated in a wide variety of pharmacological effects, such as anti-inflammatory, antiviral, and antitumor activities. However, its role in RCC remains unknown. In this study, we found that emodin effectively killed renal cancer cells without significant toxicity to noncancerous cell HK-2. Flow cytometry assay with Annexin V-FITC and PI demonstrated that emodin induces necroptosis, but not apoptosis, in renal cancer cells. Meanwhile, the phosphorylation levels of RIP1 and MLKL, the key necroptosis-related proteins, were significantly increased. To explore how emodin inhibits kidney tumor growth, we tested reactive oxygen species (ROS) levels and found that the levels of ROS increased upon emodin treatment in a dose-dependent manner. Further studies demonstrated that emodin induces necroptosis through ROS-mediated activation of JNK signaling pathway and also inhibits glycolysis by downregulation of GLUT1 through ROS-mediated inactivation of the PI3K/AKT signaling pathway. Our findings revealed the potential mechanisms by which emodin suppresses renal cancer cell growth and will help develop novel therapeutic approaches for patients with JNK- or PI3K/AKT-dysregulated renal cancer.
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Carcinoma de Células Renales , Emodina/farmacología , Glucólisis/efectos de los fármacos , Neoplasias Renales , Necroptosis/efectos de los fármacos , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Pinin (PNN), a desmosome associated protein, was demonstrated to be over-expressed and act as a tumor-promoting factor in ovarian cancer, hepatocellular carcinoma and colorectal cancer. However, the precise role of PNN in prostate cancer is still unknown. In the study, we reported that PNN was upregulated in prostate cancer tissues and PNN expression was positively associated with Gleason score, tumor stage and tumor metastasis. PNN promoted cell growth and tumorigenicity in vitro and in vivo, and modulated cell growth through driving G1/S transition via CDK6, CDK2, and Cyclin D1 in prostate cancer cells. Furthermore, PNN accelerated cell invasion, migration and EMT processes of prostate cancer cells, accompanied with the up-regulation of MMP-2, MMP-9, N-cadherin, Vimentin and down-regulation of E-cadherin. Mechanism study demonstrated that the proliferation- and motility-promoting effects of PNN on prostate cancer cells dependent on the activation of CREB, which was reversed by CREB inhibition. More important, PNN activated CREB via PI3K/AKT and ERK/MAPK pathway. Collectively, these findings indicated that PNN plays important roles in prostate cancer tumorigenesis and progression and it is a potential therapeutic target for prostate cancer treatment.
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OBJECTIVE: To explore the relationship between degradation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in the mouse liver and postmortem interval (PMI). METHODS: Sixty NIH mice were sacrificed by cervical dislocation and suffocation, and then placed into 10 degrees C and 25 degrees C temperature-controlling systems. The changes of GAPDH mRNA in the liver were detected by two-step fluorimetric reverse transcriptase polymerase chain reaction (RT-PCR) technique and nucleic acids protein cryoscope from 0 to 48 h postmortem. RESULTS: In the mouse liver, the amplification products of GAPDH mRNA could be examined within 48 h postmortem in 10 degrees C temperature-controlling system and within 36 h postmortem in 25 degrees C temperature-controlling system. The amplification products showed a decreasing tendency. CONCLUSION: Degradation of GAPDH mRNA in the mouse liver is negative correlation with PMI. GAPDH mRNA could be a new marker for estimation of PMI.
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Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Hígado/metabolismo , Cambios Post Mortem , Estabilidad del ARN , Animales , Femenino , Patologia Forense , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Masculino , Ratones , Ratones Endogámicos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Regresión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Temperatura , Factores de TiempoRESUMEN
BACKGROUND: The receptor-interacting protein kinase 3 (RIP3/RIPK3) was recently found to be a critical regulator of programmed necrosis/necroptosis. However, the biological role and clinical significance of RIP3 in prostate cancer remain obscure. METHODS: Western blotting and QRT-PCR were performed to detect the level of RIP3 in prostate cancer cells. Fixed cancer tissue and normal tissue specimens were subjected to immunohistochemical analysis of RIP3. Cell migration and invasion abilities were evaluated by transwell assays. In vitro proliferative ability was examed by MTS. And in vivo nude mice model were used to evaluate the effect of RIP3 ectopic expression on proliferative capability. Cell cycle of prostate cancer cells were analyzed by flow cytometry. Changes in some related proteins caused by RIP3 overexpression were explored using Western blotting. RESULTS: RIP3 was significantly down-regulated in prostate cancer cell lines and clinical prostate tumor samples. And over-expressing RIP3 suppressed the migration and invasion of prostate cancer cells. Two important matrix metalloproteinases MMP2, MMP9 which enables the destruction of the histological barrier of tumor cell invasion and three mesenchymal markers Vimentin, fibronectin, and N-cadherin were under-expressed due to the overexpression of RIP3, but the E-cadherin level which is the epithelial marker was increased. Furthermore, our results also showed that RIP3 can inhibit the proliferation and tumorigenicity of prostate cancer cells both in vitro and in vivo by phosphorylating MLKL, which were reversed by MLKL inhibitor treatment, indicating that necroptosis was involved in cell death. CONCLUSION: Taken together, these findings indicated that RIP3 is responsible for the progression of prostate cancer, suggesting that RIP3 might have the potential to be a prognostic marker or a therapeutic target against prostate cancer.
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OBJECTIVE: To explore the feasibility of combining human patient simulator (HPS) drivers with micro-division teaching during primary resident training by George Miller' medical education step-wised principle of goal and competence. METHOD: The 20 residents from department of anesthesia who are less than 3 years in clinical training were randomized into two Groups. The all residents in Group T received HPS training, and no HPS training in Group N. In simulation system, we designed 8 programmed critical and emergency events. We disassembled and quantified the programmed design and training process with Micro-division teaching principle. The training mode was run by test-feedback-self-analysis-instructor guide-summarize-re-practice-retest. The feedback assessment from all residents were collected after finishing HPS training. RESULTS: The training score in Group T was much higher than Group N (P < 0.05). CONCLUSIONS: The training mode with HPS is an accessory teaching means because it can improve clinical thinking and skill training of primary resident.
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Simulación por Computador , Educación Médica Continua , Medicina de Emergencia/educación , Capacitación en Servicio , Médicos , Humanos , Programas InformáticosRESUMEN
OBJECTIVE: To investigate the applied anatomy of the proximal posterior interrosseous artery perforator flap (PIAP) and report the clinical results of repairing the soft tissue defects in hands. METHODS: Between September 2007 and January 2011, 21 patients with 24 soft tissue defects in hands were repaired with the free proximal PIAP flap transplantation. The size of the flaps ranged from 2.0 cm x 1.5cm to 7cm x 5cm. The longest length of these flaps was 9 cm. 9 flaps were dissected with one additional superficial vein to anastomose with the superficial vein at the recipient sites. RESULTS: 19 flaps survived completely. Bubbles and violet color happened in 4 flaps which survived finally after partial suture removal. Flap necrosis occurred in one flap. The clinical results were satisfactory after 6-25 months of following-up, and the scars at the donor sites were not obvious. CONCLUSIONS: The free PIAP flaps have constant, reliable blood supply, and good texture. It is a good option for repairing soft-tissue defects in the hands.
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Traumatismos de la Mano/cirugía , Colgajo Perforante/trasplante , Traumatismos de los Tejidos Blandos/cirugía , Antebrazo , Supervivencia de Injerto , Humanos , Colgajo Perforante/irrigación sanguínea , Colgajos QuirúrgicosRESUMEN
OBJECTIVE: To investigate the feasibility of free descending genicular artery perforator flaps in the soft tissue defects at extremities. METHODS: Ten fresh cadavers were injected with lead oxide-gelatin mixture for three-dimensional visualization reconstruction using a 16-slice spiral computed tomography scanner and specialized volume-rendering software ( Materiaise's interactive medical image control system, MIMICS). The origin, course and distribution of the perforators in the thigh and leg region were observed. 11 patients with skin defects at the distal part of extremities were treated. The flap size ranged from 5 cm x 8 cm to 6 cm x 15 cm. Six flaps were pedicled with the descending genicular artery and the others were pedicled with the perforator of the descending genicular artery. All flaps were transferred by end to end anastomosis. RESULTS The follow-up period ranged from 6 to 18 months. All the flaps survived. The appearance and texture of the flaps were good with sensory recovery of S3. CONCLUSIONS: Free descending genicular artery perforator flap has a reliable blood supply and suitable thickness for the treatment of soft tissue defects at extremities. The technique is easily performed with reliable results.
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Extremidades/lesiones , Colgajo Perforante/irrigación sanguínea , Colgajo Perforante/trasplante , Traumatismos de los Tejidos Blandos/cirugía , Arterias , Cadáver , Estudios de Factibilidad , Estudios de Seguimiento , Humanos , Pierna , Muslo , Extremidad SuperiorRESUMEN
BACKGROUND: A number of studies have examined the association between estrogen receptor alpha (ESR-α) gene polymorphisms and bone mineral density (BMD), but previous studies of ESR-α gene XbaI (rs9340799) and PvuII (rs2234693) polymorphisms have been hampered by small sample size, regional restrictions and inconclusive results. Thus a meta-analysis is needed to assess their pooled effects. METHODS: This study reviewed all published articles indexed in Pubmed using the keywords in the title or abstract. All data were extracted independently by two reviewers using a standard form, the studies were meta-analyzed and minor discrepancies were resolved by authors' discussion. RESULTS: Twenty seven eligible studies involving 8467 women and 2032 men were identified. The XbaI and PvuII polymorphisms were significantly associated with BMD of the lumbar spine. XX and PP homozygotes had a protective effect in comparison with carriers of the x and p alleles, the effects were more significant in premenopausal women or Western women. At the femoral neck, the results were different. XX served as a protective factor in postmenopausal women, Western women, Western postmenopausal women, and men, while PP was likely to serve as a risk factor in Eastern women, Eastern postmenopausal women, and men. CONCLUSIONS: The XbaI polymorphism is correlated to BMD at diverse skeletal sites. PP had a protective role for the lumbar spine but might be a risk factor for the femoral neck.