Inhibition of c-Myc Oncoprotein Limits the Growth of Human Melanoma Cells by Inducing Cellular Crisis

Abstract Here, we show that inhibition of c-Myc causes a proliferative arrest of M14 melanoma cells through cellular crisis, evident by the increase in size, multiple nuclei, vacuolated cytoplasm, induction of senescence-associated β-galactosidase activity and massive apoptosis. The c-Myc-induced crisis is associated with decreased human telomerase reverse transcriptase expression, telomerase activity, progressive telomere shortening, glutathione (GSH), depletion and, increased production of reactive oxygen species. Treatment of control cells with l-buthionine sulfoximine decreases GSH to levels of c-Myc low expressing cells, but it does not modify the growth kinetic of the cells. Surprisingly, when GSH is increased in the c-Myc low expressing cells by treatment with N-acetyl-l-cysteine, cells escape crisis. To test the hypothesis that both oxidative stress and telomerase dysfunction are involved in the c-Myc-dependent crisis, we directly inhibited telomerase function and glutathione levels. Inactivation of telomerase, by expression of a catalytically inactive, dominant negative form of reverse transcriptase, reduces cellular lifespan by inducing telomere shortening. Treatment of cells with l-buthionine sulfoximine decreases GSH content and accelerates cell crisis. Analysis of telomere status demonstrated that oxidative stress affects c-Myc-induced crisis by increasing telomere dysfunction. Our results demonstrate that inhibition of c-Myc oncoprotein induces cellular crisis through cooperation between telomerase dysfunction and oxidative stress

relA over-expression reduces tumorigenicity and activates apoptosis in human cancer cells

We previously demonstrated that bcl-2 over-expression increases the malignant behaviour of the MCF7 ADR human breast cancer cell line and enhances nuclear factor-kappa B (NF-k B) transcriptional activity. Here, we investigated the direct effect of increased NF-k B activity on the tumorigenicity of MCF7 ADR cells by over-expressing the NF-k B subunit relA/p65. Surprisingly, our results demonstrated that over-expression of relA determines a considerable reduction of the tumorigenic ability in nude mice as indicated by the tumour take and the median time of tumour appearance. In vitro studies also evidenced a reduced cell proliferation and the activation of the apoptotic programme after relA over-expression. Apoptosis was associated with the production of reactive oxygen species, and the cleavage of the specific substrate Poly-ADP-ribose-polymerrase. Our data indicate that there is no general role for NF-k B in the regulation of apoptosis and tumorigenicity. In fact, even though inhibiting NF-k B activity has been reported to be lethal to tumour cells, our findings clearly suggest that an over-induction of nuclear NF-k B activity may produce the same effect. © 2001 Cancer Research Campaign http://www.bjcancer.co

Increased expression of antimüllerian hormone and its receptor in endometriosis

To evaluate antimüllerian hormone (AMH) and AMH receptor II (AMHRII) mRNA and protein expression in endometrium and in ovarian or deep lesions of women with endometriosis

The uterine junctional zone: A 3-dimensional ultrasound study of patients with endometriosis

The uterine junctional zone (JZ) alterations are correlated with adenomyosis. An accurate evaluation of the JZ may be obtained by 3-dimensional transvaginal sonography (TVS). The aim of the present prospective study was to assess the value of detectable alterations by 3-dimensional TVS of the JZ in patients with pelvic endometriosis (diagnosed by laparoscopy and histologic condition) and to compare these findings with those of women without pelvic endometriosis

Combination of the anti-CD30-auristatin-E antibody-drug conjugate (SGN-35) with chemotherapy improves antitumour activity in Hodgkin lymphoma

The antibody-drug conjugate (ADC) cAC10-vcMMAE consists of the tubulin inhibitor monomethyl auristatin E (MMAE) conjugated to the chimeric anti-CD30 monoclonal antibody cAC10. This ADC potently interferes with the growth of CD30-positive haematological tumours, including Hodgkin lymphoma (HL) and anaplastic large-cell lymphoma. This study found improved antitumour activity in a preclinical model of HL when SGN-35 was combined with chemotherapeutic regimens such as ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or gemcitabine. Improved efficacy was also observed in high tumour burden models, indicating that combining ADCs with chemotherapeutic agents may be advantageous for the treatment of patients with relapsed or refractory HL

Diagnostic accuracy of MRI in the differential diagnosis between uterine leiomyomas and sarcomas: A systematic review and meta-analysis

Background: Differential diagnosis between uterine leiomyomas and sarcomas is challenging. Magnetic resonance imaging (MRI) represents the second-line diagnostic method after ultrasound for the assessment of uterine masses. Objectives: To assess the accuracy of MRI in the differential diagnosis between uterine leiomyomas and sarcomas. Search Strategy: A systematic review and meta-analysis was performed searching five electronic databases from their inception to June 2023. Selection Criteria: All peer-reviewed observational or randomized clinical trials that reported an unbiased postoperative histologic diagnosis of uterine leiomyoma or uterine sarcoma, which also comprehended a preoperative MRI evaluation of the uterine mass. Data Collection and Analysis: Sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and area under the curve on summary receiver operating characteristic of MRI in differentiating uterine leiomyomas and sarcomas were calculated as individual and pooled estimates, with 95% confidence intervals (CI). Results: Eight studies with 2495 women (2253 with uterine leiomyomas and 179 with uterine sarcomas), were included. MRI showed pooled sensitivity of 0.90 (95% CI 0.84–0.94), specificity of 0.96 (95% CI 0.96–0.97), positive likelihood ratio of 13.55 (95% CI 6.20–29.61), negative likelihood ratio of 0.08 (95% CI 0.02–0.32), diagnostic odds ratio of 175.13 (95% CI 46.53–659.09), and area under the curve of 0.9759. Conclusions: MRI has a high diagnostic accuracy in the differential diagnosis between uterine leiomyomas and sarcomas