Statins are among the most commonly prescribed drugs, and around every fourth person above the age of 40 is on statin medication. Therefore, it is of utmost clinical importance to understand the effect of statins on cancer cell plasticity and its consequences to not only patients with cancer but also patients who are on statins. Here, we find that statins induce a partial epithelial-to-mesenchymal transition (EMT) phenotype in cancer cells of solid tumors. Using a comprehensive STRING network analysis of transcriptome, proteome, and phosphoproteome data combined with multiple mechanistic in vitro and functional in vivo analyses, we demonstrate that statins reduce cellular plasticity by enforcing a mesenchymal-like cell state that increases metastatic seeding ability on one side but reduces the formation of (secondary) tumors on the other due to heterogeneous treatment responses. Taken together, we provide a thorough mechanistic overview of the consequences of statin use for each step of cancer development, progression, and metastasis.

Lung cancer is a prevalent and lethal cancer type that leads to more deaths than the next four major cancer types combined. Metastatic cancer spread is responsible for most cancer-related deaths but the cellular changes that enable cancer cells to leave the primary tumor and establish inoperable and lethal metastases remain poorly understood. To uncover genes that are specifically required to sustain metastasis survival or growth, we performed a genome-scale pooled lentiviral-shRNA library screen in cells that represent nonmetastatic and metastatic states of lung adenocarcinoma. Mitochondrial ribosome and mitochondria-associated genes were identified as top gene sets associated with metastasis-specific lethality. Metastasis-derived cell lines in vitro and metastases analyzed ex vivo from an autochthonous lung cancer mouse model had lower mitochondrial membrane potential and reduced mitochondrial functionality than nonmetastatic primary tumors. Electron microscopy of metastases uncovered irregular mitochondria with bridging and loss of normal membrane structure. Consistent with these findings, compounds that inhibit mitochondrial translation or replication had a greater effect on the growth of metastasis-derived cells. Finally, mice with established tumors developed fewer metastases upon treatment with phenformin in vivo. These results suggest that the metastatic cell state in lung adenocarcinoma is associated with a specifically altered mitochondrial functionality that can be therapeutically exploited. Significance: This study characterizes altered mitochondria functionality of the metastatic cell state in lung cancer and opens new avenues for metastasis-specific therapeutic targeting.

Background and Objective: Analysis of reports of incidents, involving ABO incompatibility suggests that the main problem is poor interpretation of the pretransfusion bedside compatibility test (PBCT). We studied sources of error as experienced by nurses as to the blood groups of donor blood and of the recipient. Materials and Methods: According to their seniority in the profession and on the ward, 48 nurses were randomly selected from four transfusion sectors of the University Hospital of Grenoble, France. Each nurse interpreted 24 photos of PBCTs, including some with procedural irregularities, and was asked to assess the compatibility of the blood types of the donor and the recipient. At random, half the nurses were provided with a diagram to facilitate interpretation. Results: The overall frequency of errors was 39.8%. Errors were fewer when the tests were interpreted as compatible (7.3%) or incompatible (6.3%), and when the nurse had been in the profession between 3 and 5 years and in the ward less than 3 years (25.5%), or worked in hematology (34.7%) or anesthesia (36.5%). Use of the diagram limited the number of errors, provided the test was interpretable (22.2%). Conclusion: PBCTs cannot be considered a valid safety procedure. We need other, more effective methods to reduce the risk of incompatibility accidents.

International audienc

Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question.

A family has been observed which a gene for heterocellular hereditary persistence of fetal hemoglobin (HPFH), probably identical to that previously described as Swiss type HPFH, has been inherited together with beta-thalassemia. The interaction of these two genes resulted in beta-thalassemia heterozygotes with unusually high levels of fetal hemoglobin (3.6-6.15), heterogeneously distributed. Globin synthesis studies showed a similar degree of chain imbalance in the heterocellular HPFH-beta thalassemia compound heterozygotes and in the heterozygous beta-thalassemia member of the family. On the basis of the pattern of genetic transmission of these two characters it can be concluded that the HPFH determinant does not behave as an allele of the gamma beta delta complex.

<p>Supplementary Data Table S9</p>

<p>Supplementary Data Tables S3,S4,S5,S6</p>