No abstract

This is a repository copy of Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms.

JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, β1 and β2, may contribute to CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1- (VCAM1-) and intercellular adhesion molecule 1-coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of β1 and β2 integrins for their respective ligands. For β1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti-VLA-4 and anti-β2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-β2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.

Campylobacter jejuni is one of the leading infectious causes of food-borne illness around the world. Its ability to persistently colonize the intestinal tract of a broad range of hosts, including food-producing animals, is central to its epidemiology since most infections are due to the consumption of contaminated food products. Using a highly saturated transposon insertion library combined with next-generation sequencing and a mouse model of infection, we have carried out a comprehensive genome-wide analysis of the fitness determinants for growth in vitro and in vivo of a highly pathogenic strain of C. jejuni. A comparison of the C. jejuni requirements to colonize the mouse intestine with those necessary to grow in different culture media in vitro, combined with isotopologue profiling and metabolic flow analysis, allowed us to identify its metabolic requirements to establish infection, including the ability to acquire certain nutrients, metabolize specific substrates, or maintain intracellular ion homeostasis. This comprehensive analysis has identified metabolic pathways that could provide the basis for the development of novel strategies to prevent C. jejuni colonization of food-producing animals or to treat human infections.

Background Proximal humeral fractures are mainly associated with osteoporosis and are becoming more common with the aging of our society. The best surgical approach for internal fixation of displaced proximal humeral fractures is still being debated. Questions/purposes In this prospective randomized study, we aimed to investigate whether the deltoid-split approach is superior to the deltopectoral approach with regard to (1) complication rate; (2) shoulder function (Constant score); and (3) pain (visual analog scale [VAS]) for internal fixation of displaced humeral fractures with a polyaxial locking plate.Methods We randomized 120 patients with proximal humeral fractures to receive one of these two approaches (60 patients for each approach). We prospectively documented demographic and perioperative data (sex, age, fracture type, hospital stay, operation time, and fluoroscopy time) as well as complications. Followup examinations were conducted at 6 weeks, 6 months, and 12 months postoperatively, including radiological and clinical evaluations (Constant score, activities of daily living, and pain [VAS]). Baseline and perioperative data were comparable for both approaches. The sample size was chosen to provide 80% power, but it reached only 68% as a result of the loss of followups to detect a 10-point difference on the Constant score, which we considered the minimum clinically important difference. Results Complications or reoperations between the approaches were not different. Eight patients in the deltoid-split group (14%) needed surgical revisions compared with seven patients in the deltopectoral group (13%; p = 1.00). Deltoid-split and deltopectoral approaches showed similar Constant scores 12 months postoperatively (Deltoid-split 81; 95% confidence interval [CI], 74-87 versus deltopectoral 73; 95% CI, 64-81; p = 0.13), and there were no differences between the groups in terms of pain at 1 year (deltoid-split 1.8; 95% CI, 1.2-1.4 versus deltopectoral 2.5; 95% CI, 1.7-3.2; p = 0.14). No learning-curve effects were noted; fluoroscopy use during surgery and function and pain scores during followups were similar among the first 30 patients and the next 30 patients treated in each group. Conclusions The treatment of proximal humeral fractures with a polyaxial locking plate is reliable using both approaches. For a definitive recommendation for one of these approaches, further studies with appropriate sample size are necessary.