Choline is an essential anabolic substrate for the synthesis of phospholipids. Choline kinase phosphorylates choline to phosphocholine that serves as a precursor for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the synthesis of lipid signaling molecules. Nuclear magnetic resonance (NMR)-based metabolomic studies of human tumors have identified a marked increase in the intracellular concentration of phosphocholine relative to normal tissues. We postulated that the observed intracellular pooling of phosphocholine may be required to sustain the production of the pleiotropic lipid second messenger, phosphatidic acid. Phosphatidic acid is generated from the cleavage of phosphatidylcholine by phospholipase D2 and is a key activator of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT survival signaling pathways. In this study we show that the steady-state concentration of phosphocholine is increased by the ectopic expression of oncogenic H-Ras V12 in immortalized human bronchial epithelial cells. We then find that small interfering RNA (siRNA) silencing of choline kinase expression in transformed HeLa cells completely abrogates the high concentration of phosphocholine, which in turn decreases phosphatidylcholine, phosphatidic acid and signaling through the MAPK and PI3K/AKT pathways. This simultaneous reduction in survival signaling markedly decreases the anchorage-independent survival of HeLa cells in soft agar and in athymic mice. Last, we confirm the relative importance of phosphatidic acid for this pro-survival effect as phosphatidic acid supplementation fully restores MAPK signaling and partially rescues HeLa cells from choline kinase inhibition. Taken together, these data indicate that the pooling of phosphocholine in cancer cells may be required to provide a ready supply of phosphatidic acid necessary for the feedforward amplification of cancer survival signaling pathways.

Background: Septic pulmonary embolism is a serious but uncommon syndrome posing diagnostic challenges because of its broad range of clinical presentation and etiologies.Objective: To understand the clinical and radiographic associations of septic pulmonary embolism in patients presenting to an acute care safety net hospital. Methods: We conducted a retrospective analysis of imaging and electronic health records of all patients diagnosed with septic pulmonary embolism in our hospital between January 2000 and January 2013. Results: 41 episodes of septic pulmonary embolism were identified in 40 patients aged 17 to 71 years (median 46); 29 (72%) were men. Presenting symptoms included: febrile illness (85%); pulmonary complaints (66%) including pleuritic chest pain (22%), cough (19%) and dyspnea (15%); and those related to the peripheral foci of infection (24%) and shock (19%). Sources of infection included: skin and soft tissue (44%); infective endocarditis (27%); and infected peripheral deep venous thrombosis (17%). 35/41 (85%) were bacteremic with staphylococcus aureus. All patients had peripheral nodular lesions on chest CT scan. Treatment included intravenous antibiotics in all patients. Twenty six (63%) patients required pleural drainage and/or drainage of peripheral abscesses. Seven (17%) patients received systemic anticoagulants. Eight (20%) patients died due to various complications. Conclusion: The epidemiology of septic pulmonary embolism has broadened over the past decade with an increase in identified extrapulmonary, non-cardiac sources. In the context of an extrapulmonary infection, clinical features of persistent fever, bacteremia and pulmonary complaints should raise suspicion for this syndrome, and typical findings on the chest CT scans confirm the diagnosis. Antibiotics, local drainage procedures and increasingly, anticoagulation are keys to successful outcomes.

Choline kinase-α expression and activity are increased in multiple human neoplasms as a result of growth factor stimulation and activation of cancer-related signaling pathways. The product of choline kinase-α, phosphocholine, serves as an essential metabolic reservoir for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the production of lipid second messengers. Using in silico screening for small molecules that may interact with the choline kinase-α substrate binding domain, we identified a novel competitive inhibitor, N-(3,5-dimethylphenyl)-2-[[5-(4-ethylphenyl)-1H-1,2,4-triazol-3-yl]sulfanyl] acetamide (termed CK37) that inhibited purified recombinant human choline kinase-α activity, reduced the steady-state concentration of phosphocholine in transformed cells, and selectively suppressed the growth of neoplastic cells relative to normal epithelial cells. Choline kinase-α activity is required for the downstream production of phosphatidic acid, a promoter of several Ras signaling pathways. CK37 suppressed MAPK and PI3K/AKT signaling, disrupted actin cytoskeletal organization, and reduced plasma membrane ruffling. Finally, administration of CK37 significantly decreased tumor growth in a lung tumor xenograft mouse model, suppressed tumor phosphocholine, and diminished activating phosphorylations of ERK and AKT in vivo. Together, these results further validate choline kinase-α as a molecular target for the development of agents that interrupt Ras signaling pathways, and indicate that receptor-based computational screening should facilitate the identification of new classes of choline kinase-α inhibitors.

Background: There have been an increasing number of pediatric reports of septic pulmonary embolism in the setting of septic thrombophlebitis adjacent to a primary infectious source.Methods: Retrospective review at an urban hospital. A total of five adults with a documented primary infectious source, adjacent septic thrombophlebitis and septic pulmonary embolism were identified between 2000 and 2011.Results: The predominant symptoms on presentation were fever and pleuritic chest pain, followed by chills and cough. S. aureus was the pathogen in 4 patients. Only one case had echocardiographic evidence of endocarditis. All patients received IV antibiotics and anticoagulation therapy. No new embolic events or central nervous system complications were noted.Conclusions: The triad of extrapulmonary infection, contiguous septic thrombophlebitis and septic pulmonary embolism is present in adult as well as pediatric populations. The use of systemic anticoagulation with appropriate antibiotics resulted in clinical and radiologic improvement but no significant complications.

Frequencies of micronucleated cells (MNCs) were analyzed in the exfoliated buccal mucosa of normal healthy individuals from different parts of India who were regularly using either areca nut alone, mava, tamol, tobacco with lime, dry snuff or masheri. The analyses were also carried out among oral submucous fibrosis patients who had the habit of chewing either mava or areca nut. Compared with 'no habit' healthy individuals, all the groups, irrespective of their type of habit, had significantly higher frequencies of MNCs.

No abstract

Among community-dwelling older men, the association between lower 25(OH)D and sleep apnea was largely explained by confounding by larger body mass index and neck circumference.

No abstract