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1.
目的?探讨Notch/Dll4通路中Notch1a和Dll4分子在卵巢癌组织和正常卵巢组织表达情况。方法?应用qRT-PCR技术检测39例卵巢癌(观察组)及28例正常卵巢组织(对照组)中Notch1a和Dll4中?mRNA的表达差异。结果?Notch1a在卵巢癌组织与正常卵巢组织中mRNA表达差异倍数为2.55,差异有统计学意义(P<0.05)。Dll4在卵巢癌组织与正常卵巢组织中的mRNA表达差异倍数为1.32,差异有统计学意义(P<0.05)结论?Notch1a?和Dll4可作为卵巢癌诊断的参考指标,亦可将Notch/Dll4通路作为针对卵巢癌治疗的靶标。    相似文献   

2.
抗肿瘤血管发生是一种全新的抗肿瘤治疗策略,目前研究最多的是寻找有效抗血管内皮生长因子(VEGF)信号通路的药物.然而VEGF抑制剂并不是对所有肿瘤有效,因此,有必要进一步探索血管发生的其他信号通路.目前,Dll4-Notch信号通路被认为是抗肿瘤血管发生的新靶点,而且VEGF和Dll4-Notch信号通路在多方面相互作...  相似文献   

3.
Among proteins in the c-Myc/Max/Mad/Sin3 regulatory complex, Mad4 and Sin3B are routinely detected in human glioblastoma multiforme (GBM) cell lines. In response to gamma radiation, the expression of Sin3B and Mad4 in GBM cells was upregulated in parallel over time, suggesting that Sin3B may play a role in the regulation of Mad4 stability. In agreement with this hypothesis, exogenously expressed Sin3B significantly stabilized co-transfected Mad4 and, to a lesser extent, endogenous Mad4. In addition, siRNA silencing of Sin3B induced an increase in the expression of c-Myc and Sin3A, which contributed to increased expression of Mad4. Simultaneous silencing of Sin3B, Sin3A and c-Myc decreased Mad4 stability to a greater extent than silencing of Sin3B alone. Although Mad1 was reported to be a target of c-IAP1 E3 ligase activity for degradation, the E3 ligase activity of c-IAP1 was not required for downregulation of Mad4 expression. The association of c-IAP1 with Sin3B or Mad4 suggested that Sin3B might interfere with the binding of c-IAP1 to Mad4; however, overexpression of Sin3B did not affect the interaction between Mad4 and c-IAP1. Instead, direct binding of Sin3B to c-IAP1 may protect Mad4 from degradation by c-IAP1, leading to enhanced stability of Mad4. Exogenous expression of Sin3B also inhibited c-IAP1-mediated degradation of Mad1, TRAF2, c-IAP2 and ASK1, known targets of c-IAP1 E3 ligase activity. These results indicate that Sin3B, together with other c-Myc regulatory members, maintain the steady-state level of Mad4, in part through inhibition of c-IAP1-mediated degradation of Mad4.  相似文献   

4.

Background

Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults, but its etiology still remains unknown. Recently, a role of viruses such as cytomegalovirus and JC virus in gliomagenesis has been suggested. Since human papillomavirus (HPV) is considered the most common oncogenic virus in humans, we evaluated its occurrence in GBM samples.

Material and Methods

Fifty-two formalin-fixed paraffin-embedded primary glioblastoma specimens were retrospectively analyzed. The presence of HPV genome on tumor DNA was assessed by MY/GP nested PCR. Confirmation of HPV detection was obtained by chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) with an antibody directed against the L1 capsidic protein. Finally, univariate and multivariate proportional-hazards models were used to compare the risk of death among HPV-positive and HPV-negative patients.

Results

Strikingly, viral DNA was detected after PCR in 12 cases (23%). HPV16 genome was present in 25% infected samples, whereas the remaining samples tested positive for HPV6. CISH confirmed positivity in all infected samples for which enough material was available. Moreover, IHC positivity suggested that production of viral proteins from HPV genome is an ongoing process in GBM cancer cells. Finally an association between HPV infection and a worse prognosis was found in patients upon age stratification with a univariate analysis (HR, 2.10; 95% CI, 1.00–4.44; log-rank P = .045).

Conclusions

HPV infection status may be considered an independent prognostic factor in GBM patients and suggests that prevention may be considered, should HPV be recognized as a causative agent in gliomagenesis.  相似文献   

5.
6.
Alterations in the signal transduction pathways are key mechanisms in the pathogenesis of de novo glioblastoma multiforme (GBM), which are also involved in the resistance to chemo- and radiotherapy. Here, we analyzed the methylation status and mRNA expression of suppressor of cytokine signaling (SOCS)1-2-3, 3 of the most important inhibitory molecules of the signal transduction circuitry, in 46 GBM specimens. The relationship between methylation status of SOCS1-2-3 and clinical outcome was investigated. Using methylation-specific PCR (MS-PCR) and sequencing, after bisulphite modification, we found that the promoter of SOCS1-2-3 was methylated in 24, 6.5 and 35% of GBM, respectively. Real-time analysis showed that in methylated GBM, mRNA expression for SOCS1-2-3 was reduced by 5, 3 and 7-folds, respectively, when compared with unmethylated GBM. Moreover, methylation of SOCS3 promoter significantly associated with an unfavorable clinical outcome (p < 0.0002). Our data suggest that methylation of SOCS3 may be involved in the pathogenesis of GBM and in the resistance of this neoplasm to conventional treatment.  相似文献   

7.
Despite advances in neurosurgery and radiotherapy, the prognosis of patients with glioblastoma multiforme remains poor. Reports in the literature about the radiosensitizing properties of paclitaxel stimulated the authors to conduct a study using paclitaxel concurrently with radiation in a group of 18 patients who had residual disease postoperatively. Paclitaxel was delivered weekly as an intravenous infusion in a dose of 60 mg/m 2 along with radiation to the primary lesion. A total of 108 cycles of paclitaxel was given. All the patients tolerated the treatment well. The main side effects were haematological, and neuropathy which was self-limiting. The overall 1-year survival rate was 70%, with 12 patients alive at 13 months. The median survival has not yet been reached although it is more than 13 months. Thus, paclitaxel can be safely delivered concomitantly with radiation in patients with glioblastoma multiforme. Larger, randomized trials are required to establish the comparative efficacy of paclitaxel as a radiosensitizer in glioblastoma multiforme.  相似文献   

8.
The objective of this study was to test the predictive value of serial MRI data in relation to clinical outcome for patients with glioblastoma multiforme (GBM). Sixty-four patients with newly diagnosed GBM underwent conventional MRI and diffusion-weighted and perfusion-weighted imaging postsurgery and prior to radiation/chemotherapy (pre-RT), immediately after RT (post-RT), and every 1-2 months thereafter until tumor progression, up to a maximum of 1 year. Tumor volumes and perfusion and diffusion parameters were calculated and subject to time-independent and time-dependent Cox proportional hazards models that were adjusted for age and MR scanner field strength. Larger volumes of the T2 hyperintensity lesion (T2ALL) and nonenhancing lesion (NEL) at pre-RT, as well as increased anatomic volumes at post-RT, were associated with worse overall survival (OS). Higher normalized cerebral blood volumes (nCBVs), normalized peak height (nPH) and normalized recirculation factors (nRF) at pre-RT, and nCBV at post-RT, in the T2ALL and NEL, were associated with shorter progression-free survival (PFS). From pre- to post-RT, there was a reduction in nCBV and nPH and an increase in apparent diffusion coefficient (ADC). Patients with lower nRF values at pre-RT, or a larger increase in nRF from pre-RT to post-RT, had significantly longer PFS. Time-dependent analysis showed that patterns of changes in ADC and anatomic volumes were associated with OS, while changes in nCBV, nPH, and the contrast-enhancing volume were associated with PFS. Our studies suggest that quantitative MRI variables derived from anatomic and physiological MRI provide useful information for predicting outcome in patients with GBM.  相似文献   

9.
Background: Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in glioblastoma multiforme (GBM) and they are assigned a central role in tumor initiation, progression and relapse. The Notch pathway is important for maintenance and cell fate decisions in the normal NSC population. Notch signaling is often deregulated in GBM and recent results suggest that this pathway plays a significant role in bCSC as well. We therefore wished to further elucidate the role of Notch activation in GBM-derived bCSC. Methods: Human-derived GBM xenograft cells were cultured as NSC-like neurosphere cultures. Notch modulation was accomplished either by blocking the pathway using the γ-secretase inhibitor DAPT or by activating it by transfecting the cells with the constitutive active Notch-1 receptor.Results: GBM neurosphere cultures with high endogenous Notch activation displayed sensitivity toward Notch inhibition with regard to tumorigenic features as demonstrated by increased G0/G1 population and reduced colony formation capacity. Of the NSC-like characteristics, only the primary sphere forming potential was affected, while no effect was observed on self-renewal or differentiation. In contrast, when Notch signaling was activated a decrease in the G0/G1 population and an enhanced capability of colony formation was observed, along with increased self-renewal and de-differentiation.Conclusion: Based on the presented results we propose that active Notch signaling plays a role for cell growth and stem cell-like features in GBM neurosphere cultures and that Notch-targeted anti-bCSC treatment could be feasible for GBM patients with high endogenous Notch pathway activation.  相似文献   

10.
11.
目的探讨Notch1及其配体Dll4在骨肉瘤的表达及其和血管生成的关系。方法采用免疫组化SP法检测62例骨肉瘤Notch1和Dll4蛋白的表达,并根据CD34染色结果计数微血管密度(MVD)。43例骨软骨瘤标本作为对照。结果(1)Notch1和Dll4在骨肉瘤表达的阳性率为85.5%、88.7%,骨软骨瘤表达阳性率为21.2%、23.6%,差异具有显著性(P〈0.05);且Notch1和Dll4表达存在正相关(P〈0.05,r=0.842)。(2)Notch1和Dll4蛋白的阳性表达与骨肉瘤组织分化程度、Ennecking分期和有无转移密切相关(P〈0.05)。(3)Notch1或Dll4高表达组MVD显著高于低表达组(P〈0.05)。结论Notch1、Dll4在骨肉瘤组织中的表达上调与血管生成密切相关,可能在骨肉瘤发生、发展中起重要作用。  相似文献   

12.
Summary Four patients with malignant gliomas recurring after surgical resection, radiotherapy and chemotherapy were entered into a trial of immunotherapy. Partial removal of the recurrent tumors was performed and autologous mononuclear cell infusions were given into the resection cavity via a subgaleal reservoir that had been inserted at the time of tumor resection. Mononuclear cells were obtained using a cell separator and Ficoll-hypaque separation techniques. Patients were followed carefully with clinical examinations, CT brain scans and immunological testing. All patients have died and complete autopsies were done. We looked specifically for evidence of mononuclear cell penetration into the tumor and possible adverse effects on the normal brain or in the rest of the body. The results indicate that this type of therapy can be performed safely and may be useful in the treatment of patients with malignant gliomas.  相似文献   

13.
14.
Tumor necrosis, enhancement, and associated edema in patients with glioblastoma multiforme (GBM) represent biological variables that can be quantitated on preoperative MRI scans. We reviewed 48 highly selected patients, all of whom had supratentorial lesions, had undergone gross total tumor resection, and had received adjuvant treatments (radio- and chemotherapies). None of these patients had had surgery for recurrent tumor resection and none had harbored multifocal tumors. The median age was 50 years. The median Karnofsky performance score was 80. Multivariate analysis using the Cox regression model revealed that the strongest prognostic variable was the amount of tumor necrosis on preoperative scan (P < 0.001), with median survivals of 42, 24, 15, and 12 months for tumor necrosis grades of 0 (7 pts), I (11 pts),11 (9 pts), and III (21 pts), respectively. The intensity of enhancement of the tumor nodule was another prognostic factor (P = 0.003), with median survivals of 35, 18, and 13.5 months for enhancement grades of 0 (2 pts), I (22 pts), and II (24 pts), respectively. The extent of peritumoral edema had a quadratic effect (P = 0.001), with grades I (19 pts), II (22 pts), and III (7 pts) surviving for 24,12, and 20 months respectively. Location and volume of tumors were not statistically significant predictors of survival (P < 0.05). In conclusion, in this highly selected group, GBM patients with little or no necrosis and with less tumor nodule enhancement on preoperative MRI survive longer than patients with greater amounts of necrosis and greater degrees of tumor enhancement. In addition, a moderate degree of peritumoral edema is associated with worse prognosis.  相似文献   

15.
This phase II study aimed at determining the efficacy and safety of irinotecan combined with thalidomide in adults with recurrent glioblastoma multiforme (GBM) not taking enzyme-inducing anticonvulsants (EIACs). Adult patients (> or =18 years) with recurrent GBM with up to three relapses following surgery and radiation therapy were eligible for this trial. The primary end point was rate of progression-free survival at 6 months (PFS-6); secondary end points were response rate, overall survival, and toxicity. Patients were treated in 6-week cycles with 125 mg/m(2) irinotecan weekly for 4 weeks followed by 2 weeks off treatment and 100 mg of thalidomide daily increased as tolerated to 400 mg/day. Of 32 evaluable patients, 8 (25%) were alive and progression free at 6 months. The median PFS was 13 weeks. One patient experienced a complete response, one a partial response, and 19 stable disease. Median overall survival time from entry into the study was 36 weeks, and the 1-year survival rate was 34%. Adverse events (grade 3 or 4) included diarrhea, abdominal cramps, lymphopenia, neutropenia, and fatigue. Two of the four deaths that occurred were possibly due to treatment-related toxicity. The combination of irinotecan, a cytotoxic agent, and thalidomide, an antiangiogenic agent, shows promising activity against recurrent GBM in patients not receiving EIACs and warrants further study. The results also provide support for similar strategies using combination therapies with newer targeted antiangiogenic agents to generate effective therapies against malignant gliomas.  相似文献   

16.
17.
Delta(9)-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15-33). Delta(9)-Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.  相似文献   

18.

Background

To examine the efficacy of valproic acid (VPA) given either with or without levetiracetam (LEV) on seizure control and on survival in patients with glioblastoma multiforme (GBM) treated with chemoradiation.

Methods

A retrospective analysis was performed on 291 patients with GBM. The efficacies of VPA and LEV alone and as polytherapy were analyzed in 181 (62%) patients with seizures with a minimum follow-up of 6 months. Cox-regression survival analysis was performed on 165 patients receiving chemoradiation with temozolomide of whom 108 receiving this in combination with VPA for at least 3 months.

Results

Monotherapy with either VPA or LEV was instituted in 137/143 (95.8%) and in 59/86 (68.6%) on VPA/LEV polytherapy as the next regimen. Initial freedom from seizure was achieved in 41/100 (41%) on VPA, in 16/37 (43.3%) on LEV, and in 89/116 (76.7%) on subsequent VPA/LEV polytherapy. At the end of follow-up, seizure freedom was achieved in 77.8% (28/36) on VPA alone, in 25/36 (69.5%) on LEV alone, and in 38/63 (60.3%) on VPA/LEV polytherapy with ongoing seizures on monotherapy. Patients using VPA in combination with temozolomide showed a longer median survival of 69 weeks (95% confidence interval [CI]: 61.7–67.3) compared with 61 weeks (95% CI: 52.5–69.5) in the group without VPA (hazard ratio, 0.63; 95% CI: 0.43–0.92; P = .016), adjusting for age, extent of resection, and O6-DNA methylguanine-methyltransferase promoter methylation status.

Conclusions

Polytherapy with VPA and LEV more strongly contributes to seizure control than does either as monotherapy. Use of VPA together with chemoradiation with temozolomide results in a 2-months’ longer survival of patients with GBM.  相似文献   

19.
BACKGROUND: XR5000 is a tricyclic carboxamide that intercalates DNA and inhibits both topoisomerase I and II. The aim of this study was to evaluate the efficacy and tolerability of XR5000 in patients with recurrent glioblastoma multiforme previously untreated with chemotherapy at relapse. PATIENTS AND METHODS: Patients received XR5000 at a dose of 3010 mg/m2 as a 120-h central venous infusion every 3 weeks. An independent panel assessed response every two cycles using McDonald's criteria (tumour size, steroid intake and neurological status); toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 2.0. RESULTS: Sixteen patients were enrolled (one ineligible patient was excluded from efficacy evaluation). Performance status was zero (five patients), one (nine patients) or two (one patient). They received 30 cycles of XR5000 (median 2, range 1-5). Haematological toxicity was mild, with only one patient experiencing grade 3 neutropenia. Other related grade 3/4 adverse events included chest pain (one patient), axillary vein thrombosis (one patient) and rigors/fever in the absence of neutropenia (one patient). There were no objective responses, 14 patients progressing on XR5000 and one having stable disease. CONCLUSIONS: Although XR5000 was generally well tolerated, these results do not support further evaluation in patients with glioblastoma multiforme using this dose and schedule.  相似文献   

20.

Background

Glioblastoma multiforme (GBM) is a rare tumor, which affects 1/100 000 individuals, but it represents 30% of central nervous system malignancies. GBM is a severe tumor responsible for 2% of all cancer-related deaths. Although characterized by genotypic and phenotypic heterogeneities, GBM invariably resists conventional chemo- and radiotherapies. Several chromosome alterations and gene mutations were detected in GBM. Simian virus 40 (SV40), a small DNA tumor virus, has been found in GBM specimens by some studies, while other investigations have not confirmed the association.

Methods

An indirect enzyme-linked immunosorbent assay with 2 synthetic peptides mimicking SV40 antigens of viral capsid proteins 1–3 was employed to detect specific antibodies against SV40 in serum samples from GBM-affected patients, together with controls represented by patients affected by breast cancer and normal subjects of the same median age.

Results

Our data indicate that in serum samples from GBM-affected patients (n = 44), the prevalence of antibodies against SV40 viral capsid protein antigens is statistically significantly higher (34%, P = .016 and P = .03) than in the control groups (15%), represented by healthy subjects (n = 101) and patients affected by breast cancer (n = 78), respectively.

Conclusion

Our data indicate that SV40, or a closely related yet undiscovered human polyomavirus, is associated with a subset of GBM and circulates in humans. Our study can be transferred to the clinical oncology application to discriminate different types of heterogeneous GBM, which in turn may address an innovative therapeutic approach to this fatal cancer.  相似文献   

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