Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML

Applying Quality Control Charts to the Analysis of Single-Subject Data Sequences

Techniques from the field of quality control can be used to classify the quality of individual samples of physical or cognitive performance. After stable baselines have been established for an individual, deviations in performance can be evaluated using control charts. The effectiveness of this approach in evaluating cognitive performance was tested using databases collected under a variety of risk factors. The sensitivity and specificity characteristics of Shewhart, cumulativesum (CUSUM), and exponentially weighted moving average (EWMA) control charts were determined for a total of 174 trials involving 10 participants and 23 cognitive performance assessment measures. The most effective technique in each case was typically a function of the specific performance measure and the type of performance change being evaluated. Sensitivity and specificity for the best techniques were as high as 100%. This study demonstrated the usefulness of quality control charts as a tool to evaluate individual participant performance over time. Actual or potential applications of this research include readiness-to-perform screening of industrial workers in order to improve the health and safety of the workforce.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

A case study of Kanban implementation within the Pharmaceutical Supply Chain

The paper explores the implementation of the kanban system, which is a Lean technique, within the Pharmaceutical Supply Chain (PSC). The case study provides insight to the benefits and challenges arising from the application of this technique, within a group of cooperative pharmacists, in Greece. The research questions developed from the review of the literature were tested using evidence from field-based, action research within a pharmaceutical organisation. The reported case study contributes to the longer term debate on assessing the Lean maturity level within the healthcare sector. There are two primary findings: i) that the adoption of kanban system provides a strategic benefit and improves the quality of services. ii) it also provides a basis for a strategy of operational change; it gives the opportunity to the organisation to move away from the current push delivery and logistics systems toward improved logistics strategy models

Peasant settlers and the ‘civilizing mission’ in Russian Turkestan, 1865-1917

This article provides an introduction to one of the lesser-known examples of European settler colonialism, the settlement of European (mainly Russian and Ukrainian) peasants in Southern Central Asia (Turkestan) in the late nineteenth and early twentieth centuries. It establishes the legal background and demographic impact of peasant settlement, and the role played by the state in organising and encouraging it. It explores official attitudes towards the settlers (which were often very negative), and their relations with the local Kazakh and Kyrgyz population. The article adopts a comparative framework, looking at Turkestan alongside Algeria and Southern Africa, and seeking to establish whether paradigms developed in the study of other settler societies (such as the ‘poor white’) are of any relevance in understanding Slavic peasant settlement in Turkestan. It concludes that there are many close parallels with European settlement in other regions with large indigenous populations, but that racial ideology played a much less important role in the Russian case compared to religious divisions and fears of cultural backsliding. This did not prevent relations between settlers and the ‘native’ population deteriorating markedly in the years before the First World War, resulting in large-scale rebellion in 1916