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Wind Upchurch posted an update 6 months, 1 week ago
Published by BMJ.A 41-year-old male patient presented with isolated right lower limb swelling. An ultrasound scan showed right external iliac and femoral vein deep vein thrombosis due to extrinsic compression by an aneurysm of the right common iliac artery. Investigations including imaging and a tissue biopsy of right and left femoral arteries confirmed a rare clinical presentation of fibromuscular dysplasia involving iliac, coeliac, renal and pulmonary vessels. The common iliac artery aneurysm was successfully treated with endovascular repair. Six months later, he developed coronary artery involvement with spontaneous dissection of left anterior descending artery diagnosed on coronary angiogram which was managed conservatively. At 6-year follow-up, he remains clinically asymptomatic and continues with regular surveillance imaging. Iliac arterial fibromuscular dysplasia is uncommon and clinical presentation with a complication such as a deep vein thrombosis is atypical. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.A 72-year-old man presented to our service with sudden onset right-sided weakness, aphasia and gaze palsy with diplopia. CT angiogram demonstrated an acute thrombotic occlusion of the distal basilar artery, a basilar infarct and the patient underwent successful thrombectomy. ECG and telemetry demonstrated slow atrial fibrillation (AF). His transthoracic echocardiogram (TTE) showed a reduced ejection fraction of 25% with global hypo-kinesis, a dilated left ventricle (LV) and LV hypertrophy (LVH). Repeat TTE appeared suspicious for an infiltrative cardiomyopathy with LVH and a speckled appearance to the myocardium. Approximately 10 months later, he suffered another ischaemic stroke post-elective cardioversion for AF while on anticoagulation. Cardiac MRI demonstrated areas of delayed gadolinium enhancement consistent with amyloidosis. Fat pad biopsy was positive for amyloidosis. Our patient has made an excellent recovery from the ischaemic strokes and is being managed in our heart failure clinic. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.PURPOSE Poor prognosis of patients with muscle-invasive bladder cancer (BC) that often metastasizes drives the need for discovery of molecular determinants of BC progression. Chondroitin sulfate proteoglycans, including CD44, regulate cancer progression; however, the identity of a chondroitinase (Chase) that cleaves chondroitin sulfate from proteoglycans is unknown. HYAL-4 is an understudied gene suspected to encode a Chase, with no known biological function. We evaluated HYAL-4 expression and its role in BC. EXPERIMENTAL DESIGN In clinical specimens HYAL-4 wild-type (Wt) and V1 expression was evaluated by RT-qPCR, immunohistochemistry and/or immunoblotting; a novel assay measured Chase activity. Wt and V1 were stably expressed or silenced in normal urothelial and three BC cell lines. Transfectants were analyzed for stem cell phenotype, invasive signature and tumorigenesis, and metastasis in four xenograft models, including orthotopic bladder. RESULTS HYAL-4 expression, specifically a novel splice variant (V1), was elevated in bladder tumors; Wt expression was barely detectable. V1 encoded a truncated 349 amino acid protein that was secreted. In BC tissues, V1 levels associated with metastasis and cancer-specific-survival with high efficacy and encoded Chase activity. V1 cleaved chondroitin-6-sulfate from CD44, increasing CD44 secretion. V1 induced stem cell phenotype, motility/invasion, and an invasive signature. CD44 knockdown abrogated these phenotypes. V1-expressing urothelial cells developed angiogenic, muscle-invasive tumors. V1-expressing BC cells formed tumors at low-density and formed metastatic bladder tumors when implanted orthotopically. SAHA inhibitor CONCLUSIONS Our study discovered the first naturally-occurring eukaryotic/human Chase and connected it to disease pathology, specifically cancer. V1-Chase is a driver of malignant BC and potential predictor of outcome in BC patients. Copyright ©2020, American Association for Cancer Research.Geranylgeranoic acid (GGA) originally was identified in some animals and has been developed as an agent for preventing second primary hepatoma. We previously have identified GGA also as an acyclic diterpenoid in some medicinal herbs. Recently, we reported that in human hepatoma-derived HuH-7 cells, GGA is metabolically labeled from 13C-mevalonate. Several cell-free experiments have demonstrated that GGA is synthesized through geranylgeranial by oxygen-dependent oxidation of geranylgeraniol (GGOH), but the exact biochemical events giving rise to GGA in hepatoma cells remain unclear. Monoamine oxidase B (MAOB) has been suggested to be involved in GGOH oxidation. Here, using two human hepatoma cell lines, we investigated whether MAOB contributes to GGA biosynthesis. Using either HuH-7 cell lysates or recombinant human MAOB, we found (i) that the MAO inhibitor tranylcypromine dose-dependently down-regulates endogenous GGA levels in HuH-7 cells, and (ii) that siRNA-mediated MAOB silencing reduces intracellular GGA levels in HuH-7 and Hep3B cells. Unexpectedly, however, CRISPR/Cas9-generated MAOB-knockout human hepatoma Hep3B (MAOB-KO) cells had GGA levels similar to those in MAOB wild-type cells. A sensitivity of GGA levels to siRNA-mediated MAOB down-regulation was recovered when the MAOB-KO cells were transfected with a MAOB-expression plasmid, suggesting that MAOB is the enzyme primarily responsible for GGOH oxidation and that some other latent metabolic pathways may maintain endogenous GGA levels in the MAOB-KO hepatoma cells. Along with the previous findings, these results provide critical insights into the biological roles of human MAOB and provide evidence that hepatic MAOB is involved in endogenous GGA biosynthesis via GGOH oxidation. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Photoreceptors have high energy-demands and a high density of mitochondria that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) of fuel substrates. Although glucose is the major fuel for central nervous system (CNS) brain neurons, in photoreceptors (also CNS), most glucose is not metabolized through OXPHOS but is instead metabolized into lactate by aerobic glycolysis. The major fuel sources for photoreceptor mitochondria remained unclear for almost six decades. Similar to other tissues (like heart and skeletal muscle) with high metabolic rates, photoreceptors were recently found to metabolize fatty acids (palmitate) through OXPHOS. Disruption of lipid entry into photoreceptors leads to extracellular lipid accumulation, suppressed glucose transporter expression, and a duel lipid/glucose fuel shortage. Modulation of lipid metabolism helps restore photoreceptor function. However, further elucidation of the types of lipids used as retinal energy sources, the metabolic interaction with other fuel pathways, as well as the crosstalk among retinal cells to provide energy to photoreceptors is not yet known.
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