Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review

Clinicians can use biomarkers to guide therapeutic decisions in estrogen receptor positive (ER+) breast cancer. One such biomarker is cellular proliferation as evaluated by Ki-67. This biomarker has been extensively studied and is easily assayed by histopathologists but it is not currently accepted as a standard. This review focuses on its prognostic and predictive value, and on methodological considerations for its measurement and the cut-points used for treatment decision. Data describing study design, patients’ characteristics, methods used and results were extracted from papers published between January 1990 and July 2010. In addition, the studies were assessed using the REMARK tool. Ki-67 is an independent prognostic factor for disease-free survival (HR 1.05–1.72) in multivariate analyses studies using samples from randomized clinical trials with secondary central analysis of the biomarker. The level of evidence (LOE) was judged to be I-B with the recently revised definition of Simon. However, standardization of the techniques and scoring methods are needed for the integration of this biomarker in everyday practice. Ki-67 was not found to be predictive for long-term follow-up after chemotherapy. Nevertheless, high KI-67 was found to be associated with immediate pathological complete response in the neoadjuvant setting, with an LOE of II-B. The REMARK score improved over time (with a range of 6–13/20 vs. 10–18/20, before and after 2005, respectively). KI-67 could be considered as a prognostic biomarker for therapeutic decision. It is assessed with a simple assay that could be standardized. However, international guidelines are needed for routine clinical use

The HIV-1 transcriptional activator Tat has potent nucleic acid chaperoning activities in vitro

The human immunodeficiency virus type 1 (HIV-1) is a primate lentivirus that causes the acquired immunodeficiency syndrome (AIDS). In addition to the virion structural proteins and enzyme precursors, that are Gag, Env and Pol, HIV-1 encodes several regulatory proteins, notably a small nuclear transcriptional activator named Tat. The Tat protein is absolutely required for virus replication since it controls proviral DNA transcription to generate the full-length viral mRNA. Tat can also regulate mRNA capping and splicing and was recently found to interfere with the cellular mi- and siRNA machinery. Because of its extensive interplay with nucleic acids, and its basic and disordered nature we speculated that Tat had nucleic acid-chaperoning properties. This prompted us to examine in vitro the nucleic acid-chaperoning activities of Tat and Tat peptides made by chemical synthesis. Here we report that Tat has potent nucleic acid-chaperoning activities according to the standard DNA annealing, DNA and RNA strand exchange, RNA ribozyme cleavage and trans-splicing assays. The active Tat(44–61) peptide identified here corresponds to the smallest known sequence with DNA/RNA chaperoning properties

Etude de l'interaction de protéines rétrovirales du VIH-1 avec leurs cibles biologiques

Les protéines NCp7 et Tat du VIH-1 constituent des cibles pour de nouveaux traitements.Grâce à ses propriétés chaperonnes, NCp7 stimule le premier et le second saut de brin de la transcription inverse, en favorisant l hybridation des séquences nucléiques TAR et PBS, respectivement. Nos études ont montré que i) les déterminants structuraux des activités chaperonnes portés par les deux doigts de zinc de NCp7 se retrouvent en partie dans le doigt unique et les domaines basiques adjacents de la NCp10 du MoMuLV, ii) NCp7 induit une déstabilisation limitée des séquences PBS, et active la formation d homodimères boucle-boucle, ce qui est de nature à accroître la variabilité génétique du virus.Nous avons également montré que la liaison du zinc replie localement Tat, lui permettant d induire la formation de microtubules stabilisés in vitro. Ainsi, la Tat zinguée serait la forme active in vivo, capable d induire l apoptose des lymphocytes T sains en inhibant la dépolymérisation des microtubules.NCp7 and Tat proteins represent ideal targets for new antiretroviral agents.Due to its chaperone activity, NCp7 stimulates the first and the second strand transfer during reverse transcription, by activating the annealing of the TAR and PBS sequences, respectively. We showed that i) the structural determinants of the chaperone activities scattered on the two NCp7 zinc fingers are partly encoded by the unique finger of MoMuLV NCp10 and its flanking basic domains, ii) NCp7 induces a limited destabilization of the PBS sequences, and directs the formation of kissing homodimers which could contribute to the viral genetic diversity.Then, we showed that zinc binding induces a local folding of the Tat peptide, enabling Tat to promote the formation of stable microtubules in vitro. Thus, the zinc bound Tat is likely the active form in vivo, able to induce apoptosis in non infected T-lymphocytes by preventing the microtubule depolymerisation.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF