Chronic Myeloid Leukemia Patient Registry in the Russian Federation: From Observational Studies to the Efficacy Evaluation in Clinical Practice

Background. Due to the significant increase in life expectancy and the quality of life in patients with chronic myeloid leukemia (CML) as well as the growing need for expensive tyrosine kinase inhibitors (TKI), the analysis of cost-effectiveness and lifelong monitoring of patients is especially important. Aim. We present the results of a multicenter observational study “The Russian Registry of Chronic Myeloid Leukemia in routine clinical practice (2011–2016)”. Materials & Methods. The study included Russian patients with CML, confirmed by the detection of a Ph-chromosome or a BCR-ABL transcript. The statistical analysis (July 1, 2016) included 7609 patients from 80 regions of the Russian Federation (covering 95 % of the population). The annual increase in the number of patients with newly diagnosed CML was 600–650 patients. At the time of the statistical analysis, 6995 (92 %) patients remained under observation, 473 (6 %) died and 141 (2 %) were withdrawn. The registry included 44 % of men and 56 % of women, the median age was 49 years (range 2–94 years). The peak incidence (46.3 %) occurred at the age of 40–60 years. The median disease duration by the time of the analysis was 6 years (range 0.1–30 years). Results. The disease was diagnosed in the chronic phase (CP), acceleration phase, and blast crisis in 6560 (93.8 %), 380 (5.5 %) and 47 (0.7 %) patients, respectively. The proportion of risk groups according to Sokal for low, intermediate and high risk in CP was 49 %, 30 %, and 21 %, respectively. TKI were administered to 6473 (92.5 %) patients. Imatinib and the second generation TKI (TKI2) were administered to 5570 (86 %) and 903 (14 %) patients, respectively. The total of 30.4 % of patients received the increased imatinib dose of 600–800 mg. In the TKI2 group, 558 (61.7 %) patients received nilotinib and 345 (38.2 %) patients received dasatinib. The proportion of patients with completed molecular genetic studies (MGS) in 2014, 2015 and the first 6 months of 2016 amounted to 61 %, 58 % and 23 %, respectively. The proportion of patients with cytogenetic studies (CS) for the same period was 28 %, 26 % and 7 %, respectively. No CS or MGS data were presented for 34 %, 35 % and 63 % of patients during this period. Optimal molecular response and major molecular response (MMR) for TKI therapy were observed in 23 % and 58 % of patients treated 12 months, respectively. When nilotinib was used in the second line, MMR was obtained in 42 % of patients, and a deep molecular response was obtained in 25 % of patients (BCR-ABL < 0.01 %). Conclusion. The high efficacy of TKI therapy was observed in the majority of patients with the possibility of achieving a minimal residual disease. The problems concerning untimely monitoring and suboptimal administration of second line treatment were identified. In general, the CML patient registry allowed the data integration of data and information management of population with CML in Russia

In vitro nuclear interactome of the HIV-1 Tat protein

<p>Abstract</p> <p>Background</p> <p>One facet of the complexity underlying the biology of HIV-1 resides not only in its limited number of viral proteins, but in the extensive repertoire of cellular proteins they interact with and their higher-order assembly. HIV-1 encodes the regulatory protein Tat (86–101aa), which is essential for HIV-1 replication and primarily orchestrates HIV-1 provirus transcriptional regulation. Previous studies have demonstrated that Tat function is highly dependent on specific interactions with a range of cellular proteins. However they can only partially account for the intricate molecular mechanisms underlying the dynamics of proviral gene expression. To obtain a comprehensive nuclear interaction map of Tat in T-cells, we have designed a proteomic strategy based on affinity chromatography coupled with mass spectrometry.</p> <p>Results</p> <p>Our approach resulted in the identification of a total of 183 candidates as Tat nuclear partners, 90% of which have not been previously characterised. Subsequently we applied <it>in silico </it>analysis, to validate and characterise our dataset which revealed that the Tat nuclear interactome exhibits unique signature(s). First, motif composition analysis highlighted that our dataset is enriched for domains mediating protein, RNA and DNA interactions, and helicase and ATPase activities. Secondly, functional classification and network reconstruction clearly depicted Tat as a polyvalent protein adaptor and positioned Tat at the nexus of a densely interconnected interaction network involved in a range of biological processes which included gene expression regulation, RNA biogenesis, chromatin structure, chromosome organisation, DNA replication and nuclear architecture.</p> <p>Conclusion</p> <p>We have completed the <it>in vitro </it>Tat nuclear interactome and have highlighted its modular network properties and particularly those involved in the coordination of gene expression by Tat. Ultimately, the highly specialised set of molecular interactions identified will provide a framework to further advance our understanding of the mechanisms of HIV-1 proviral gene silencing and activation.</p