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OBJECTIVE: To investigate the safety and clinical effect of testis-sparing microsurgery (TSMS) in the treatment of benign testis tumor (BTT). METHODS: We retrospectively analyzed the clinical data on 16 cases of BTT treated in the Department of Andrology of the Affiliated Hospital of Qingdao University from October 2020 to February 2023. The median age of the patients was 23 years. All the tumors were unilateral, 7 in the left and 9 in the right side, with a median diameter of 1.85 cm (1.0ï¼3.5 cm). The patients all underwent color Doppler flow imaging (CDFI), MRI, semen analysis and examination of serum T, alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH), followed by TSMS. The boundaries between the tumors and normal testis tissue were accurately identified under the microscope, and the tumors and the adjacent normal testis tissue 2 mm from their margins were excised completely. Bipolar coagulation forceps were used for wound hemostasis to maximally preserve the normal testis tissue. The resected specimens were subjected to fast frozen pathology intraoperatively, and the patients were followed up for 14ï¼40 months by regular scrotal CDFI, MRI and examinations of serum T and semen parameters. RESULTS: The levels of serum T, AFP, HCG and LDH and semen parameters were all within the normal range preoperatively. TSMS were successfully completed in all the cases, and all were pathologically confirmed as BTT according to the latest edition of WHO Classification of Tumors: Urinary and Male Genital Tumors. CDFI showed normal blood supply within the testis tissue at 1 month after surgery. No signs of intra-testicular tumor residue, recurrence or metastasis, nor significant changes in the levels of serum T, AFP, HCG or LDH or semen parameters were observed during the follow-up as compared with the baseline. Natural conception was achieved in 2 cases at 16 and 18 months respectively after surgery. CONCLUSION: BTT can be differentially diagnosed by CDFI and MRI before surgery and confirmed by histopathology. TSMS can achieve complete excision of the tumor, maximal sparing of the normal testis tissue and thereby effective preservation of male fertility.
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Microcirurgia , Neoplasias Testiculares , Testículo , Humanos , Masculino , Microcirurgia/métodos , Neoplasias Testiculares/cirurgia , Estudos Retrospectivos , Adulto Jovem , Testículo/cirurgia , Adulto , alfa-Fetoproteínas/análise , Tratamentos com Preservação do Órgão/métodosRESUMO
Background: Randomized controlled trials (RCTs) have demonstrated that combining Chinese herbal injections (CHIs) with oxaliplatin plus tegafur (SOX) chemotherapy regimens improves clinical effectiveness and reduces adverse reactions in patients with advanced gastric cancer (AGC). These RCTs highlight the potential applications of CHIs and their impact on AGC patient prognosis. However, there is insufficient comparative evidence on the clinical effectiveness and safety of different CHIs when combined with SOX. Therefore, we performed a network meta-analysis to rank the clinical effectiveness and safety of different CHIs when combined with SOX chemotherapy regimens. This study aimed to provide evidence for selecting appropriate CHIs in the treatment of patients with AGC. Methods: We searched eight databases from their inception until March 2023. Surface Under the Cumulative Ranking Curve (SUCRA) probability values were used to rank the treatment measures, and the Confidence in Network Meta-Analysis (CINeMA) software assessed the grading of evidence. Results: A total of 51 RCTs involving 3,703 AGC patients were identified. Huachansu injections + SOX demonstrated the highest clinical effectiveness (SUCRA: 78.17%), significantly reducing the incidence of leukopenia (93.35%), thrombocytopenia (80.19%), and nausea and vomiting (95.15%). Shenfu injections + SOX improved Karnofsky's Performance Status (75.59%) and showed a significant reduction in peripheral neurotoxicity incidence (88.26%). Aidi injections + SOX were most effective in reducing the incidence of liver function damage (75.16%). According to CINeMA, most confidence rating results were classified as "low". Conclusion: The combination of CHIs and SOX shows promising effects in the treatment of AGC compared to SOX alone. Huachansu and Shenfu injections offer the greatest overall advantage among the CHIs, while Aidi injections are optimal for reducing the incidence of liver damage. However, further rigorous RCTs with larger sample sizes and additional pharmacological studies are necessary to reinforce these findings.
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BACKGROUND: Hypoxia is a hallmark of solid tumors and leads to the metabolic reprogramming of cancer cells. The role of epigenetic regulation between hypoxia and aberrant cholesterol metabolism in colorectal cancer (CRC) remains elusive. METHODS: Hypoxia-responsive circular RNAs (circRNAs) were identified by high throughput RNA sequencing between CRC cells cultured under normoxia or hypoxia. The protein-coding potential of circINSIG1 was identified by polysome profiling and LC-MS. The function of circINSIG1 was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses. RESULTS: A novel hypoxia-responsive circRNA named circINSIG1 was identified, which was upregulated in CRC tissues and correlated with advanced clinical stages and poor survival. Mechanistically, circINSIG1 encoded a 121 amino acid protein circINSIG1-121 to promote K48-linked ubiquitination of the critical cholesterol metabolism regulator INSIG1 at lysine 156 and 158 by recruiting CUL5-ASB6 complex, a ubiquitin E3 ligase complex, thereby inducing cholesterol biosynthesis to promote CRC proliferation and metastasis. The orthotopic xenograft tumor models and patient-derived xenograft models further identified the role of circINSIG1 in CRC progression and potential therapeutic target of CRC. CONCLUSIONS: circINSIG1 presents an epigenetic mechanism which provides insights into the crosstalk between hypoxia and cholesterol metabolism, and provides a promising therapeutic target for the treatment of CRC.
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Colesterol , Neoplasias Colorretais , RNA Circular , Humanos , Proliferação de Células , Colesterol/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteínas Culina/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Hipóxia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Ubiquitina/metabolismoRESUMO
The direct cross-couplings of diaryl sulfoxides with aryl bromides via C-S bond cleavage could be readily accomplished using nickel(II) as the catalyst, 1,2-bis(diphenylphosphino)ethane (dppe) as the ligand, and magnesium turnings as the reducing metal in THF, leading to the corresponding biaryls in moderate to good yields. The reaction exhibited a broad substrate scope and could be applied to a gram-scale synthesis. The "one-pot" reaction, which avoids the utility of presynthesized and moisture-labile organometallic compounds, is operationally simple and step-economic.
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Objective: Glioblastoma is one of the most common malignant tumors in the brain, and these glioblastoma patients have very poor prognosis. Ferroptosis is involved in the progression of various tumors, including the glioblastoma. This study aims to determine the involvement of microRNA (miR)-147a in regulating ferroptosis of glioblastoma in vitro. Methods: Human glioblastoma cell lines were transfected with the inhibitor, mimic and matched negative controls of miR-147a in the presence or absence of ferroptotic inducers. To knock down the endogenous solute carrier family 40 member 1 (SLC40A1), cells were transfected with the small interfering RNA against SLC40A1. In addition, cells with or without the miR-147a mimic treatment were also incubated with temozolomide (TMZ) to investigate whether miR-147a overexpression could sensitize human glioblastoma cells to TMZ chemotherapy in vitro. Results: We found that miR-147a level was decreased in human glioblastoma tissues and cell lines and that the miR-147a mimic significantly suppressed the growth of glioblastoma cells in vitro. In addition, miR-147a expression was elevated in human glioblastoma cells upon erastin or RSL3 stimulation. Treatment with the miR-147a mimic significantly induced ferroptosis of glioblastoma cells, and the ferroptotic inhibitors could block the miR-147a mimic-mediated tumor suppression in vitro. Conversely, the miR-147a inhibitor prevented erastin- or RSL3-induced ferroptosis and increased the viability of glioblastoma cells in vitro. Mechanistically, we determined that miR-147a directly bound to the 3'-untranslated region of SLC40A1 and inhibited SLC40A1-mediated iron export, thereby facilitating iron overload, lipid peroxidation, and ferroptosis. Furthermore, miR-147a mimic-treated human glioblastoma cells exhibited higher sensitivity to TMZ chemotherapy than those treated with the mimic control in vitro. Conclusion: We for the first time determine that miR-147a targets SLC40A1 to induce ferroptosis in human glioblastoma in vitro.
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Proteínas de Transporte de Cátions/metabolismo , Ferroptose , Glioblastoma , MicroRNAs , Linhagem Celular Tumoral , Ferroptose/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Temozolomida/farmacologia , Temozolomida/uso terapêuticoRESUMO
Our study aims to estimate the incidence of metachronous second primary lung cancer(SPLC) in initial primary lung cancer(IPLC) survivors and to determine whether radiotherapy affects the risk of metachronous SPLC in the first five years after the diagnosis of lung cancer. Incidence data of IPLC individuals who survived ≥2 years were obtained from SEER-18 database in 2004-2007. Joinpoint regression analysis and competing risk analysis were used to calculate the incidence of metachronous SPLC. Propensity score matching and decision analysis were available to estimate the effect of radiotherapy on metachronous SPLC. 264 of 11657 IPLC survivors with radiotherapy and 1090 of 24499 IPLC survivors without radiotherapy developed metachronous SPLC during 5-year follow-up, respectively. In joinpoint regression analysis, the 5-year incidence of metachronous SPLC in the radiotherapy group was lower than that in the nonradiotherapy group(2385 per 100,000 vs 4748 per 100,000, HR = 0.43,95% CI:0.39-0.47). Competing risk analysis showed that the survivors with radiotherapy were associated with the lower 5 year incidence of metachronous SPLC compared with those without radiotherapy(2.28% vs 4.47%, HR = 0.49,95% CI:0.43-0.57). Through propensity score matching, 4077 pairs of survivors were available to further study that radiotherapy potentially decreased the risk of developing metachronous SPLC with the adjustment of various factors(2.5% vs 3.3%, HR = 0.72, 95% CI:0.55-0.96). Decision analysis suggested that radiotherapy was a negative independent risk factor of metachronous SPLC with clinical net benefit in a range of risk thresholds (2% to 5%). Survivors of IPLC with radiotherapy likely had a low risk of metachronous SPLC during the first five years follow-up, especially non-small cell lung cancer.
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Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Segunda Neoplasia Primária/radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/patologia , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: The prognosis of lung cancer with malignant pericardial effusion is very terrible owing to the impact of cardiac tamponade. The aim of our study seeks to identify prognostic factors and establish a prognostic nomogram of non small cell lung cancer (NSCLC) with malignant pericardial effusion. METHODS: NSCLC patients with malignant pericardial effusion between 2010 and 2014 are searched from SEER database.Cancer-specific death of these patients are analyzed through the Kaplan-Meier method, Cox proportional hazard model and competing risk model. Prognostic nomogram of cancer-specific death is performed and validated with concordance index (C-index), calibration plots and internal validation population. Propensity score matching is used to evaluate whether chemotherapy affected the survival of study population. RESULTS: 696 eligible NSCLC patients are involved in the study population, with 22.7% of 1-year survival rate and 8.9% of 2-year survival rate. Laterality, AJCC N, AJCC T, and chemotherapy are regarded as independent prognostic factors of cancer-specific death in the Cox proportional hazards model and competing risk model. The C-index of established nomogram is 0.703(95%CI:0.68-0.73) for cancer-specific death in the study population with acceptable calibration, which is significantly higher than classical TNM stage(C-index = 0.56, 95%CI:0.52-0.60). After 1:1 propensity score matching, chemotherapy potentially reduces the risk of cancer-specific death (HR = 0.42 95%CI: 0.31-0.58) of NSCLC with pericardial effusion. CONCLUSIONS: NSCLC with malignant pericardial effusion harbors low overall survival. One prognostic nomogram based on laterality, AJCC N, AJCC T and chemotherapy is developed for cancer-specific death to predict 1-year and 2-year survival rate with good performance.
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Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Nomogramas , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/mortalidade , Idoso , Calibragem , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Tamponamento Cardíaco/complicações , Tamponamento Cardíaco/diagnóstico , Causas de Morte , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Derrame Pericárdico/fisiopatologia , Prognóstico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Programa de SEER , Taxa de Sobrevida , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: This study was designed to estimate the trends in 5-year incidence of metachronous second primary lung cancer(SPLC) and to establish a risk prediction model to identify candidates who were at high risk of developing metachronous SPLC. METHODS: Incidence data between 2004 and 2007 were obtained from SEER database, including 42453 participants who survived ≥ 2 years after the initial diagnosis of lung cancer. Joinpoint regression analysis was used to calculate the 5-year incidence rates of metachronous SPLC per 100 000 population. Related risk factors of the survivors who developed MSPLC during five years were identified through logistic regression analysis, followed by establishment of risk prediction nomogram. Discrimination (C-index), calibration and decision analysis were further performed to assess the validation and clinical net benefit of risk prediction nomogram. RESULTS: A total of 1412 survivors with lung cancer developed MSPLC during five years, with 3546 per 100 000 population of age-adjusted 5-year incidence. Age, histology, tumor stage, and radiation were recognized as risk factors of metachronous SPLC, as indicated by logistic regression analysis. The risk prediction nomogram of metachronous SPLC harbored moderate discrimination(C-index = 0.67) and good calibration, with the risk of 0.01 to 0.11.The decision curve analysis showed that clinical net benefit of this risk prediction nomogram in a range of risk thresholds (0.01 to 0.06) was higher compared to all-screening or no-screening strategies. CONCLUSIONS: Collectively, the cumulative risk of metachronous SPLC of the survivors increased over time. The risk prediction nomogram was available to select high-risk survivors who should regularly undergo computed tomography screening.
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Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias Pulmonares/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Nomogramas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Medição de RiscoRESUMO
The proliferative activity of hepatic carcinoma cells is directly associated with tumorigenesis, tumor development, metastasis and invasion. A variety of cytokines and peptides serve important roles in the development of hepatic carcinoma. The aim of the present study was to examine the effect of intermedin (IMD) on hepatic carcinoma cell proliferation and its mechanism of action. HepG2 hepatic carcinoma cell lines were treated with human recombinant IMD1-53 and its receptor antagonist IMD17-47. Cell proliferation was detected using a Cell Counting kit-8. The activation of the classical Wnt signaling pathway was demonstrated by the ratio of TOPflash:FOPflash luciferase activity. The expression of c-Myc and cyclin D1 downstream of the Wnt signaling pathway were detected using reverse transcription-quantitative polymerase chain reaction analysis. It was demonstrated that IMD may promote the proliferation of HepG2 cells in a time-dependent manner, and that the IMD receptor antagonist IMD17-47 could eliminate this promotion. IMD may activate classical Wnt signaling pathway transcriptional activity and the mRNA levels of certain downstream target genes. Furthermore, blocking of the Wnt signaling pathway may inhibit IMD-induced HepG2 cell proliferation to a certain extent. IMD may promote hepatic carcinoma cell proliferation by binding with receptor antagonist IMD17-47 and activating the Wnt signaling cascade, thus providing a novel avenue for the treatment of hepatic carcinoma.
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OBJECTIVE: MicroRNAs (miRNAs) plays an important role in the development of malignant carcinoma. The small peptide intermedin (IMD) can promote hepatic carcinoma cell proliferation. The aim of the present study is to examine the effect of miR-155 on IMD-stimulated hepatic carcinoma cell proliferation. METHODS: Proliferation of hepatic carcinoma SMMC7721 cells was detected by CCK-8, expression of proliferating cell nuclear antigen (PCNA) and miR-155 was detected by real-time PCR. RESULTS: We found that IMD promotes the proliferation of SMMC7721 cells in a time and dose-dependent manner. IMD can upregulate the expression of miR-155, and blocking of miR-155 can inhibit the IMD-induced SMMC7721 cell proliferation to some extent. CONCLUSION: This study demonstrated that IMD can promote the proliferation of human hepatic carcinoma cell line SMMC7721 cells through upregulation of miR-155. This study may contribute to hepatic cancer prevention and therapy.
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Estrogen receptor beta (ERß) has been shown to play a therapeutic role in inflammatory bowel disease (IBD). However, the mechanism underlying how ERß exerts therapeutic effects and its relationship with P2X3 receptors (P2X3R) in rats with inflammation is not known. In our study, animal behavior tests, visceromotor reflex recording, and Western blotting were used to determine whether the therapeutic effect of ERß in rats with inflammation was related with P2X3R. In complete Freund adjuvant (CFA)-induced chronic inflammation in rats, paw withdrawal threshold was significantly decreased which were then reversed by systemic injection of ERß agonists, DPN or ERB-041. In 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, weight loss, higher DAI scores, increased visceromotor responses, and inflammatory responses were reversed by application of DPN or ERB-041. The higher expressions of P2X3R in dorsal root ganglia (DRG) of CFA-treated rats and those in rectocolon and DRG of TNBS-treated rats were all decreased by injection of DPN or ERB-041. DPN application also inhibited P2X3R-evoked inward currents in DRG neurons from TNBS rats. Mechanical hyperalgesia and increased P2X3 expression in ovariectomized (OVX) CFA-treated rats were reversed by estrogen replacements. Furthermore, the expressions of extracellular signal-regulated kinase (ERK) in DRG and spinal cord dorsal horn (SCDH) and c-fos in SCDH were significantly decreased after estrogen replacement compared with those of OVX rats. The ERK antagonist U0126 significantly reversed mechanical hyperalgesia in the OVX rats. These results suggest that estrogen may play an important therapeutic role in inflammation through down-regulation of P2X3R in peripheral tissues and the nervous system, probably via ERß, suggesting a novel therapeutic strategy for clinical treatment of inflammation.
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Receptor beta de Estrogênio/agonistas , Estrogênios/farmacologia , Inflamação/metabolismo , Limiar da Dor/efeitos dos fármacos , Receptores Purinérgicos P2X3/metabolismo , Animais , Feminino , Hiperalgesia/metabolismo , Nitrilas/farmacologia , Oxazóis/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
This study investigated the expression of nucleolin in tissue samples in patients with non-small cell lung cancer (NSCLC). Nucleolin was studied to determine whether it has a prognostic value and if its levels correlate with various clinicopathologic parameters. The relationship between nucleolin and expression of DNA-PKcs was also evaluated. Immunohistochemistry was used for detecting the expression levels of nucleolin and DNA-PKcs in tissues from 225 stage IA to IIIB NSCLC patients who underwent lung surgery. Nucleolin was observed predominantly in the cytoplasm, and some levels were observed in the nucleus. Nucleolin expression was higher in NSCLC tissues than adjacent normal lung tissues. Among 225 NSCLC patients, 117 (52.0 %) had high expression of nucleolin. The expression of nucleolin was significantly associated with pathologic stage (P = 0.013) and T status (P = 0.043). Multivariate analysis revealed that nucleolin, cytoplasmic nucleolin, and nuclear nucleolin expression were independent prognostic factors for both overall survival (OS) (P < 0.001) and disease-free survival (DFS) (P < 0.001). A high level of nuclear nucleolin served as an independent prognostic factor for better survival, while a high level of cytoplasmic nucleolin was closely associated with worse prognosis in NSCLC patients. The expression of nucleolin and cytoplasmic nucleolin positively correlated with DNA-PKcs (P < 0.001). These data suggest that nucleolin could be an effective treatment target and prognostic factor for patients with NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/patologia , Proteína Quinase Ativada por DNA/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Nucleares/metabolismo , Fosfoproteínas/biossíntese , Proteínas de Ligação a RNA/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , NucleolinaRESUMO
Growing evidence reported that Golgi phosphoprotein 3 (GOLPH3) was involved in the progression of several human cancers. To determine whether knockout of GOLPH3 enhances the effect of Chemotherapy against cell growth of oral squamous cell carcinoma in vitro. OSCC cells were transfected with Golph3 plasmid, Golph3-RNAi and the relative control plasmids. Transfected Tca-8113 cells treated with cis-Dichlorodiamineplatinum (DDP; 0, 0.05, 0.25, 1.25, 6.25 and 31.25 ug/ml) or Paclitaxe (0, 2, 10, 50, 250 and 1250 nM) or Adriamycin (0, 0.25, 0.5, 1, 2 and 4 ug/ml) for 24 h, respectively, was determined using MTT assay. Apoptosis-related protein expression Cytochrome-C, Caspase3 and Bcl-2 was analyzed by RT-PCR and western blots. Result of MTT showed that Golph3-RNAi transfected Tca-8113 cells enhanced the effect of chemotherapy, and the effect was strengthened with the increasing concentration of drugs, and the Golph3 plasmid transfected Tca-8113 cells showed the opposite effect. RT-PCR and western blots assays revealed that expression of cytochrome-C and caspase3 were up-regulated, while Bcl-2 expression was down-regulated in Golph3-RNAi transfected Tca-8113 cells. Taken together, this study demonstrated that GOLPH3 had potent pro-tumor growth and decreased the effect of Chemotherapy, and its mechanism is primarily via cell anti-apoptosis, down-regulating the expression of cytochrome-C and caspase3, up-regulating Bcl-2 expression.
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The present study aimed at identifying cell cycle inhibitors from the fermentation broth of Streptomyces pseudoverticillus YN17707. Activity-guided isolation was performed on tsFT210 cells. Compounds were isolated through various chromatographic methods and elucidated by spectroscopic analyses. Flow cytometry was used to evaluate the cell cycle inhibitory activities of the fractions and compounds. Two compounds were obtained and identified as pteridic acid hydrate (1) and pteridic acid C (2), which arrested the tsFT210 cells at the G0/G1 phase with the MIC values being 32.8 and 68.9 µmol·L(-1), respectively. These results provide a basis for future development of Compounds 1 and 2 as novel cell cycle inhibitors for cancer therapy.
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Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ácidos Heptanoicos/isolamento & purificação , Compostos de Espiro/isolamento & purificação , Streptomyces/química , Linhagem Celular , Ácidos Heptanoicos/química , Ácidos Heptanoicos/farmacologia , Humanos , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/farmacologiaRESUMO
Oct4 protein encoded by POU5F1 plays a pivotal role in maintaining the selfrenewal of pluripotent stem cells; however, its presence in cancer cells remains controversial. In the present study, we provided evidence that the transcripts of authentic OCT4 gene (OCT4A) and its multiple pseudogenes were detected in a variety of cancer cell lines. A few major bands were also detected by western blotting using an antiOct4A monoclonal antibody. Moreover, an antiOct4pT235 antibody was used to identify a band in the majority of the tested cancer cell lines that coincided with one of the antiOct4A bands which was decreasable by a specific shRNA. The Oct4pT235 signals were also detected in human glioblastoma and liver cancer specimens by immunofluorescence microscopy and immunohistochemistry. U87 glioblastoma cells were cultured in a neural stem cell medium to induce the formation of neurospheres rich in stemlike cancer cells. The levels of Oct4pT235 in the sphere cells were markedly increased compared to their monolayer parental cells, a result that was accompanied by upregulation of the PI3KAkt pathway. Akti1/2, a specific inhibitor of Akt, effectively reduced the level of Oct4pT235 and attenuated the proliferation of U87 sphere cells. ITE, an agonist of the aryl hydrocarbon receptor, also significantly attenuated the Aktmediated phosphorylation of Oct4 in glioblastoma and liver cancer cells, and reduced their tumorigenic potential in a xenograft tumor model. Taken together, we concluded that the Aktmediated phosphorylation of Oct4A or its homolog protein was associated with the proliferation of stemlike cancer cells that may serve as a novel biomarker and drug target for certain types of cancer.
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Glioblastoma/patologia , Proteínas de Neoplasias/fisiologia , Células-Tronco Neoplásicas/citologia , Fator 3 de Transcrição de Octâmero/metabolismo , Proteínas Proto-Oncogênicas c-akt/fisiologia , Animais , Benzilaminas/farmacologia , Neoplasias Encefálicas/química , Carcinoma Hepatocelular/química , Divisão Celular , Linhagem Celular Tumoral , Núcleo Celular/química , Meios de Cultura , Glioblastoma/química , Xenoenxertos , Humanos , Indóis/farmacologia , Neoplasias Hepáticas/química , Camundongos , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Quinoxalinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Transdução de Sinais , Esferoides Celulares , Tiazóis/farmacologiaRESUMO
A novel dual-pH sensitive charge-reversal strategy is designed to deliver antitumor drugs targeting to tumor cells and to further promote the nuclei internalization by a stepwise response to the mildly acidic extracellular pH (≈6.5) of a tumor and endo/lysosome pH (≈5.0). Poly(L-lysine)-block-poly(L-leucine) diblock copolymer is synthesized and the lysine amino residues are amidated by 2,3-dimethylmaleic anhydride to form ß-carboxylic amide, making the polypeptides self-assemble into negatively charged micelles. The amide can be hydrolyzed when exposed to the mildly acidic tumor extracellular environment, which makes the micelles switch to positively charged and they are then readily internalized by tumor cells. A nuclear targeting Tat peptide is further conjugated to the polypeptide via a click reaction. The Tat is amidated by succinyl chloride to mask its positive charge and cell-penetrating function and thus to inhibit nonspecific cellular uptake. After the nanoparticles are internalized into the more acidic intracellular endo/lysosomes, the Tat succinyl amide is hydrolyzed to reactivate the Tat nuclear targeting function, promoting nanoparticle delivery into cell nuclei. This polypeptide nanocarrier facilitates tumor targeting and nuclear delivery simultaneously by simply modifying the lysine amino residues of polylysine and Tat into two different pH-sensitive ß-carboxylic amides.
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Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Peptídeos/química , Transporte Ativo do Núcleo Celular , Núcleo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Micelas , Peptídeos/síntese química , Polilisina/química , Multimerização Proteica , Produtos do Gene tat do Vírus da Imunodeficiência Humana/químicaRESUMO
OBJECTIVE: Compared with uterine artery embolism (UAE), we aimed to investigate the efficacy and safety of transvaginal debridement and repair surgery (TDRS) and analyze the association between postoperative recovery and individual related factors. METHODS: A total of 128 patients diagnosed with cesarean scar pregnancy (CSP) from January 2006 to June 2014 were divided into 2 groups. Group A: 38 cases were treated with UAE. Group B: 90 cases were treated with TDRS, of whom 41 received preoperative chemotherapy. RESULTS: The failure rate in Group A was 5.3% (2/38) and the 2 cases of secondary vaginal hemorrhage after UAE were cured by hysterectomy and TDRS respectively. All patients were successfully treated in Group B and the postoperative outcomes of the patients who received preoperative chemotherapy showed no statistically differences compared with those who didn't. The hospital stays, serumß-hCG and menstruation recovery in Group B were significantly shorter than those in Group A (P<0.001). In Group B, there was no significant correlation between serumß-hCG recovery, menstruation recovery and individual related factors including serumß-hCG, gestational age and maximum diameter of gestational sac at diagnosis. CONCLUSION: Compared with UAE, TDRS is safer, more effective and with a rapider recovery. As an alternative therapeutic option, its prognosis isn't associated with some individual related factors. Furthermore, preoperative chemotherapy is unnecessary.
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The genomic amplification of chromosome 1q long arm, the chromosomal region containing C1orf61, is a common event in human cancers. However, the expression pattern of chromosome 1 open reading frame 61 (C1orf61) in hepatocellular carcinoma (HCC) and its effects on HCC progression remain unclear. We have previously reported that C1orf61 is highly up-regulated during human embryogenesis. In this study, we report that C1orf61 expression is associated with the progression of liver disease. We found that C1orf61 is up-regulated in hepatic cirrhosis tissues and is further up-regulated in primary HCC tumors. Moreover, hepatitis B virus (HBV)-positive patients exhibited significantly higher levels of C1orf61 expression than HBV-negative patients. The evaluation of highly malignant HCC cell lines revealed high protein expression levels of C1orf61. Furthermore, the C1orf61 protein was found to be predominantly distributed within the cytoplasm. The ectopic expression of C1orf61 in the nonmalignant L02 cell line promoted cellular proliferation and colony formation in vitro, as well as cell cycle progression via the regulation of the expression of specific cell cycle-related proteins. In addition, the overexpression of C1orf61 in L02 cells facilitated cellular invasion and metastasis. The down-regulation of epithelial markers (E-cadherin and occludin) and the up-regulation of mesenchymal markers (N-cadherin, vimentin, and snail) suggested that the overexpression of C1orf61 induced the epithelial-mesenchymal transition (EMT) that is linked to metastasis. Taken together, our findings demonstrate, for the first time, the roles of C1orf61 in HCC tumorigenesis and metastasis.
Assuntos
Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica , Neoplasias Hepáticas/patologia , Metástase Neoplásica , Sequência de Bases , Western Blotting , Carcinoma Hepatocelular/genética , Linhagem Celular , Linhagem Celular Tumoral , Primers do DNA , Feminino , Hepatite B/genética , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Masculino , Fases de Leitura Aberta , Análise Serial de TecidosRESUMO
The voltage-gated Kv1.3 K(+) channel in effector memory T cells serves as a new therapeutic target for multiple sclerosis. In our previous studies, the novel peptide ADWX-1 was designed and synthesized as a specific Kv1.3 blocker. However, it is unclear if and how ADWX-1 alleviates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. In this study, the administration of ADWX-1 significantly ameliorated the rat experimental autoimmune encephalomyelitis model by selectively inhibiting CD4(+)CCR7(-) phenotype effector memory T cell activation. In contrast, the Kv1.3-specific peptide had little effect on CD4(+)CCR7(+) cells, thereby limiting side effects. Furthermore, we determined that ADWX-1 is involved in the regulation of NF-κB signaling through upstream protein kinase C-θ (PKCθ) in the IL-2 pathway of CD4(+)CCR7(-) cells. The elevated expression of Kv1.3 mRNA and protein in activated CD4(+)CCR7(-) cells was reduced by ADWX-1 engagement; however, an apparent alteration in CD4(+)CCR7(+) cells was not observed. Moreover, the selective regulation of the Kv1.3 channel gene expression pattern by ADWX-1 provided a further and sustained inhibition of the CD4(+)CCR7(-) phenotype, which depends on the activity of Kv1.3 to modulate its activation signal. In addition, ADWX-1 mediated the activation of differentiated Th17 cells through the CCR7(-) phenotype. The efficacy of ADWX-1 is supported by multiple functions, which are based on a Kv1.3(high) CD4(+)CCR7(-) T cell selectivity through two different pathways, including the classic channel activity-associated IL-2 pathway and the new Kv1.3 channel gene expression pathway.