Cell Proliferation in the Presence of Telomerase

BACKGROUND: Telomerase, which is active early in development and later in stem and germline cells, is also active in the majority of human cancers. One of the known functions of telomerase is to extend the ends of linear chromosomes, countering their gradual shortening at each cell division due to the end replication problem and postreplication processing. Telomerase concentration levels vary between different cell types as well as between different tumors. In addition variable telomerase concentrations will exist in different cells in the same tumor when telomerase inhibitors are used, because of limitations of drug delivery in tissue. Telomerase extends short telomeres more frequently than long telomeres and the relation between the extension frequency and the telomere length is nonlinear. METHODOLOGY/PRINCIPAL FINDINGS: Here, the biological data of the nonlinear telomerase-telomere dynamics is incorporated in a mathematical theory to relate the proliferative potential of a cell to the telomerase concentration in that cell. The main result of the paper is that the proliferative capacity of a cell grows exponentially with the telomerase concentration. CONCLUSIONS/SIGNIFICANCE: The theory presented here suggests that long term telomerase inhibition in every cancer progenitor or cancer stem cell is needed for successful telomere targeted cancer treatment. This theory also can be used to plan and assess the results of clinical trials targeting telomerase

Clinical presentation, treatment modalities and outcome in patients with adrenocortical carcinoma: A single center experience

Adrenocortical carcinoma is an orphan disease usually associated with a poor prognosis. Surgery is the only treatment with a curative intent, leaving systemic therapy mainly for the purpose of symptom control. First line combination chemotherapy with Etoposide, Doxorubicin, Cisplatin and Mitotane (EDP-Mitotane) is considered the standard of care, although this regimen is not associated with an overall survival benefit. Due to the rarity of the disease no standard therapy exists in the second line or when patients are intolerant to the first line treatment. Therefore, treatment of these patients is usually following a very individual path in daily practice. Our aim was to retrospectively analyze treatment of patients with adrenocortical carcinoma in our tertiary center and compare treatment outcomes with reports in the literature. Our findings reflect the daily practice in adrenocortical carcinoma treatment and showed that surgery is the mainstay of therapy, even in some cases with metastatic disease. Adjuvant therapy in adrenocortical carcinoma was initiated less frequently than suggested by current guidelines. Furthermore, most of the patients in our cohort received more than one line of chemotherapy for metastatic or inoperable disease with overall survival rates comparable to those published. In summary, our analysis stresses the importance of clinical trial activity in this rare disease in order to standardize and improve adrenocortical carcinoma therapy more profoundly.status: publishe

A proposal of a standardised nomenclature for terminal minute sister chromatid exchanges

We described spontaneous minute sister chromatid exchanges (SCE) in telomeric regions of human and Chinese hamster ovary (CHO) chromosomes more than 10 years ago. These structures, which we called t-SCE, were detected by means of highly precise quantitative microphotometrical scanning and computer graphic image analysis. Recently, several authors using the CO-FISH method also found small SCEs in telomeric regions and called them T-SCE. The use of different terms for designating the same phenomenon should be avoided. We propose ter SCE as a uniform nomenclature for minute telomeric SCEs

Short telomeres are associated with inferior outcome, genomic complexity, and clonal evolution in chronic lymphocytic leukemia

Telomere length in chronic lymphocytic leukemia (CLL) has been shown to be of prognostic importance, but the analyses have largely been executed on heterogeneous patient cohorts outside of clinical trials. In the present study, we performed a comprehensive analysis of telomere length associations in the well characterized CLL8 trial (n = 620) of the German CLL study group, with validation in a representative cohort of the CLL4 trial (n = 293). Absolute telomere length was analyzed using quantitative-PCR. Apart from identifying associations of short telomere length with adverse prognostic factors and survival, the study identified cases with 17p- and 11q- associated with TP53 and ATM loss, respectively, to have the shortest telomeres, even when these aberrations were present in small subclones. Thus, telomere shortening may precede acquisition of the high-risk aberrations, contributing to disease evolution. In line with this, telomere shortening was associated with an increase in genomic complexity as well as clonal evolution, highlighting its importance as a biomarker especially in monitoring disease progression in non-high-risk CLL