BackgroundCombination therapy is one of the most effective tools for limiting the emergence of drug resistance in pathogens. Despite the widespread adoption of combination therapy across diseases, drug resistance rates continue to rise, leading to failing treatment regimens. The mechanisms underlying treatment failure are well studied, but the processes governing successful combination therapy are poorly understood. We address this question by studying the population dynamics of Mycobacterium tuberculosis within tuberculosis patients undergoing treatment with different combinations of antibiotics.ResultsBy combining very deep whole genome sequencing (~1000-fold genome-wide coverage) with sequential sputum sampling, we were able to detect transient genetic diversity driven by the apparently continuous turnover of minor alleles, which could serve as the source of drug-resistant bacteria. However, we report that treatment efficacy has a clear impact on the population dynamics: sufficient drug pressure bears a clear signature of purifying selection leading to apparent genetic stability. In contrast, M. tuberculosis populations subject to less drug pressure show markedly different dynamics, including cases of acquisition of additional drug resistance.ConclusionsOur findings show that for a pathogen like M. tuberculosis, which is well adapted to the human host, purifying selection constrains the evolutionary trajectory to resistance in effectively treated individuals. Nonetheless, we also report a continuous turnover of minor variants, which could give rise to the emergence of drug resistance in cases of drug pressure weakening. Monitoring bacterial population dynamics could therefore provide an informative metric for assessing the efficacy of novel drug combinations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1196-0) contains supplementary material, which is available to authorized users.

GADD45, MyD118, and CR6 (also termed GADD45␣, ␤, and ␥) comprise a family of genes that encode for related proteins playing important roles in negative growth control, including growth suppression. Data accumulated suggest that MyD118/GADD45/CR6 serve similar but not identical functions along different apoptotic and growth suppressive pathways. It is also apparent that individual members of the MyD118/GADD45/CR6 family are differentially induced by a variety of genetic and environmental stress agents. The MyD118, CR6, and GADD45 proteins were shown to predominantly localize within the cell nucleus. Recently, we have shown that both MyD118 and GADD45 interact with proliferating cell nuclear antigen (PCNA), a protein that plays a central role in DNA replication, DNA repair, and cell cycle progression, as well as with the universal cyclin-dependent kinase inhibitor p21. In this work we show that also CR6 interacts with PCNA and p21. Moreover, it is shown that CR6 interacts with PCNA via a domain that also mediates interaction of both GADD45 and MyD118 with PCNA. Importantly, evidence has been obtained that interaction of CR6 with PCNA impedes the function of this protein in negative growth control, similar to observations reported for MyD118 and GADD45 (1).

The ideal surgical treatment of giant liver hemangioma is still controversial. This study aims to compare the outcomes of enucleation with those of resection for liver hemangioma larger than 10 cm in different locations of the liver and establish the preoperative predictors of increased intraoperative blood loss.Eighty-six patients underwent enucleation or liver resection for liver hemangioma larger than 10 cm was retrospectively reviewed. Patient demographic, tumor characteristics, surgical indications, the outcomes of both surgical treatment, and the clinicopathological parameters influencing intraoperative blood loss were analyzed.Forty-six patients received enucleation and 40 patients received liver resection. Mean tumor size was 14.1 cm with a range of 10–35 cm. Blood loss, blood product usage, operative time, hepatic vascular occlusion time and frequency, complications and postsurgical hospital stay were similar between liver resections and enucleation for right-liver and left-liver hemangiomas. There was no surgery-related mortality in either group. Bleeding was more related to adjacency of major vascular structures than the size of hemangioma. Adjacency to major vascular structures and right or bilateral liver hemangiomas were independently associated with blood loss >550 mL (P = 0.000 and 0.042, respectively).Both enucleation and liver resection are safe and effective surgical treatments for liver hemangiomas larger than 10 cm. The risk of intraoperative blood loss is related to adjacency to major vascular structures and the location of hemangioma.