Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer.

BACKGROUND: Effective treatment for patients with advanced thyroid cancer is lacking. Metabolism reprogramming is required for cancer to undergo oncogenic transformation and rapid tumorigenic growth. Glutamine is frequently used by cancer cells for active bioenergetic and biosynthetic needs. This study aims to investigate whether targeting glutamine metabolism is a promising therapeutic strategy for thyroid cancer. METHODS: The expression of glutaminase (GLS) and glutamate dehydrogenase (GDH) in thyroid cancer tissues was evaluated by immunohistochemistry, and glutamine metabolism-related genes were assessed using real time-qPCR and western blotting. The effects of glutamine metabolism inhibitor 6-diazo-5-oxo-l-norleucine (DON) on thyroid cancer cells were determined by CCK-8, clone formation assay, Edu incorporation assay, flow cytometry, and Transwell assay. The mechanistic study was performed by real time-qPCR, western blotting, Seahorse assay, and gas chromatography-mass spectrometer assay. The effect of DON prodrug (JHU-083) on thyroid cancer in vivo was assessed using xenograft tumor models in BALB/c nude mice. RESULTS: GLS and GDH were over-expressed in thyroid cancer tissues, and GLS expression was positively associated with lymph-node metastasis and TNM stage. The growth of thyroid cancer cells was significantly inhibited when cultured in glutamine-free medium. Targeting glutamine metabolism with DON inhibited the proliferation of thyroid cancer cells. DON treatment did not promote apoptosis, but increased the proportion of cells in the S phase, accompanied by the decreased expression of cyclin-dependent kinase 2 and cyclin A. DON treatment also significantly inhibited the migration and invasion of thyroid cancer cells by reducing the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Non-essential amino acids, including proline, alanine, aspartate, asparagine, and glycine, were reduced in thyroid cancer cells treated with DON, which could explain the decrease of proteins involved in migration, invasion, and cell cycle. The efficacy and safety of DON prodrug (JHU-083) for thyroid cancer treatment were verified in a mouse model. In addition to suppressing the proliferation and metastasis potential of thyroid cancer in vivo, enhanced innate immune response was also observed in JHU-083-treated xenograft tumors as a result of decreased expression of cluster of differentiation 47 and programmed cell death ligand 1. CONCLUSIONS: Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.

Spontaneous closure of ventricular septal defects in the first year of life.

BACKGROUND AND PURPOSE: The recent increase in the prevalence of ventricular septal defect (VSD) has been ascribed to the improved detection of small defects with echocardiography and the wider use of screening. The aim of this study was to determine the prevalence and timing of spontaneous closure of specific types of VSD in neonates using echocardiographic screening and follow-up. METHODS: Two-dimensional color Doppler echocardiography was performed in 3,472 clinically normal full-term neonates born at Cathay General Hospital to detect isolated VSD. The relative prevalence of muscular versus perimembranous defects and their outcome in the first year of life were evaluated. RESULTS: VSD was found in 74 neonates (34 male, 40 female), resulting in a prevalence of 21.3/1,000 live births. There were 48 muscular, 25 perimembranous, and one subpulmonic defects. Of the 74 patients, 11 were lost to follow-up. Within the observation period of 12 months, spontaneous closure occurred in 40 patients in the muscular group and in six patients in the perimembranous group. The overall rate of spontaneous closure was 73% by the end of the first year. Only five patients with perimembranous defects received digoxin therapy. CONCLUSIONS: The prevalence of VSD in this series of neonates was 21.3/1,000 live births. The most common location of VSD in the neonatal period was in the region of the muscular septum. Muscular defects were more likely to close spontaneously than perimembranous defects. Most muscular defects underwent spontaneous closure during the 12-month follow-up period.

Antioxidants may mitigate the deterioration of coronary arteritis in patients with Kawasaki disease unresponsive to high-dose intravenous gamma-globulin.

During the early stages of Kawasaki disease, a marked increase in oxygen-free-radicals (OFRs), which are produced by activated polymorphonuclear cells, may induce coronary arteritis. Early use of high-dose intravenous gamma-globulin (IVIG) and aspirin effectively blocked this deteriorating course of coronary arteritis; however, late use of IVIG, even using a high-dose schedule, did not achieve the same efficacy. The causes and reactions to the scenario of IVIG refractoriness have rarely been mentioned in the literature. We present an 11-month-old male infant with Kawasaki disease and deteriorating coronary arteritis owing to late use of IVIG who showed dramatic responsiveness to the addition of alpha-tocopherol and ascorbic acid. We also discuss the possible mechanism.

Central venous catheter-induced atrial ectopic tachycardia with reverse alternating Wenckebach periods.

A centrally inserted venous catheter may cause atrial ectopic tachycardia. The association of atrial ectopic tachycardia with spontaneous reverse alternating Wenckebach periodicity has rarely been reported. We describe a 4-year-old boy with tetralogy of Fallot who developed atrial ectopic tachycardia with reverse alternating Wenckebach periods postoperatively after central venous catheter placement. All such episodes emerged from a 3:2 atrioventricular block, followed by runs of 2:1 atrioventricular block with progressive shortening of the conducted PR intervals. Normal sinus rhythm returned after the catheter was withdrawn to the superior vena cava. Reverse alternating Wenckebach periodicity may be a tachycardia-dependent physiologic phenomenon.

Cardiotoxicity in imipramine intoxication: report of one case.

Imipramine is the most commonly prescribed tricyclic antidepressant of acute life threatening self-poisoning. We report a 15-month-old boy of accidental poisoning with imipramine, who developed generalized tonic-clonic convulsions and drug-related cardiac conduction abnormalities with PR prolongation, QRS widening, and QTc lengthening. The patient's imipramine level was 1389 ng/ml. The rapid resolution of intraventricular conduction delay and normalization of the QRS-T complexes after gastric lavage, installation of activated charcoal and alkalinization of the blood strongly implicates imipramine intoxication in the etiology of the cardiotoxicity. The patient made a full recovery without neurological sequelae.

Multi-undulant T-U-wave, sinus bradycardia and long QT syndrome: a possible phenotype of mutant genes controlling the inward potassium rectifiers.

Inward rectifying potassium currents (Ikr and Iks) during phase 3 repolarization of the myocyte from the beginning to the end of repolarization of the myocardial syncytium will inscribe a T-U-wave on the surface electrocardiogram (ECG). Type two congenital long QT syndrome (LQT2) is a phenotype of human ether-a-go-go-related gene (HERG) mutation on the chromosome 7q 35-36. Type one congenital long QT syndrome (LQT1) is a phenotype of KvLQT1 mutation on the chromosome 11p15.5. Both LQT1 and LQT2 relate with inward rectifying potassium currents and is repolarization related, therefore, it is speculate that patients of LQT1 and LQT2 may have an abnormal T-U-wave on their surface ECG. To two probands of congenital LQT, 8 patients of structural heart disease treated by open heart surgery, 13 patients of structural heart disease without open-heart surgery, and 10 patients of normal controls, 24 hour-Holter monitoring was performed from July to December 1996. Their corrected QT interval (QTc) as well as the RR interval of every heart beat was calculated by a computer. The results showed that all 33 patients exhibited beat-by-beat fluctuation of their QTc and RR daily. The RR intervals of these two probands of congenital LQT were somewhile more than 1200 ms during circadian waking time, while 31 cases without LQT showed their RR prolongation only during the circadian sleeping time. A multi-undulant T-U-wave, or a beat-to-beat changing of vectors or amplitudes of their T-U-wave observed in these two probands of congenital LQT, were not observable in those 31 patients without congenital LQT. Therefore, we concluded that multi-undulant T-U-wave, sinus bradycardia and a longer QTc was a phenotype of the mutated genes which control the inward rectifying potassium currents during phase 3 repolarization.

Prognostic value of color Doppler echocardiographic findings in premature newborns with patent ductus arteriosus.

This study intended to evaluate the relationship between the prognosis for premature newborns (PM) with patient ductus arteriosus (PDA) and their Doppler echocardiographic findings. From January 1989 to December 1995, of 369 premature newborns in their first postnatal week, 196 underwent ductal evaluations echocardiographically: 47 of these 196 cases were found to have PDA. Each echocardiogram had complete data for cardiac output, ejection fraction, the left atrial-to-the-aortic ratio (LA/AO), the systolic time interval of the right ventricle (RVSTI), the transvalvular pressure gradient from tricuspid regurgitation (TGTR) and ductal Doppler color flow maps. These 47 premature newborns with PDA were grouped into (A) "asymptomatic" patients whose ductus closed spontaneously within a one-year follow-up (15 subjects), (B) "symptomatic" patients whose ductus were closed by pharmacological or surgical managements (20 subjects), and (C) "complicated" patients whose ductus caused mortality of the host (12 subjects). The remaining 149 premature newborns with a closed ductus (CD) served as controls. The RVSTI in these 47 premature newborns with PDA was found to be significantly higher than those of 149 CD (0.26 +/- 0.12 vs. 0.18 +/- 0.06, p < 0.005), and denoting that PM-PDA had a higher mean pulmonary arterial pressure. The TGTR of these 47 premature newborns with PDA was also higher than these of the 149 CD controls (30.50 +/- 11.85 mmHg vs. 20.54 +/- 6.88 mmHg, p < 0.005), denoting that PM-PDA had a higher pulmonary arterial systolic pressures. Gestational age of group C neonates was younger than group A (29.46 +/- 3.41 weeks vs. 32.80 +/- 2.78 weeks, P < 0.01). The birth weight of Group C neonates was lower than that of Group A (1366.17 +/- 684.28 gm vs. 2061.67 +/- 751.77 gm. p < 0.01), therefore, extreme prematurity and small-for-gestational-age could have increased the mortality of PM-PDA. Doppler color flow maps of group C showed a wider ductal patency, less ductal waist-narrowing, more vehement red-color forward flow and less midstream mosaicism. It was concluded that patient with extreme prematurity, with very-low-birth-weight or wider patent ductus, higher pulmonary hypertension, less midstream mosaicism, or less ductal waist-narrowing would have a poorer prognosis.

Impact of screening blood donors for hepatitis C antibody on posttransfusion hepatitis: a prospective study with a second-generation anti-hepatitis C virus assay.

BACKGROUND: Hepatitis C is the major cause of posttransfusion hepatitis. Blood components that are positive for antibody to hepatitis C virus (anti-HCV) can transmit posttransfusion hepatitis. STUDY DESIGN AND METHODS: To investigate the effect on posttransfusion hepatitis of screening blood donors with a second-generation test for anti-HCV, 249 transfusion recipients who underwent cardiovascular surgery were prospectively followed. Six recipients who were positive for anti-HCV before transfusion and 51 subjects with incomplete follow-up were excluded from this study. RESULTS: Eleven (13.8%) of 80 subjects who received unscreened blood had two successive serum alanine aminotransferase levels > 90 U per L. Seven (8.8% of total) developed anti-HCV and HCV RNA and two (2.5% of total) developed IgM antibody to cytomegalovirus (IgM anti-CMV). By contrast, 3 (2.7%) of the 112 subjects who received anti-HCV-screened blood had two successive serum alanine aminotransferase levels > 90 U per L. None of these three developed anti-HCV and HCV RNA, but two (1.8% of total) showed the development of IgM anti-CMV. The study shows that screening for anti-HCV in blood donors with a second-generation test almost abrogated posttransfusion viral hepatitis C. CONCLUSION: After anti-HCV screening, other body fluid-transmitted viruses such as CMV may become important in posttransfusion hepatitis.

Intensification of relative myocardial T2-weighted magnetic resonance signals in patients with acute viral myocarditis: report of one case.

A 10-year-old girl was admitted to our hospital because of frequent attacks of syncope over a period of two days. A physical examination, electrocardiogram, echocardiograms and a cardiac enzyme study concluded that the girl was likely to be suffering from acute viral myocarditis. Intensities of the T2-Weighted magnetic resonance signals between the myocardium and the trapezius muscle of this patient on the first, the eighth, and the twenty-eighth hospital day were 5.1, 7.8, and 3.6 respectively. These values were significantly higher than the values of seven other patients without a history of acute viral myocarditis. Therefore, we concluded that the myocardial T2-weighted signal did intensify in patients with acute viral myocarditis.

Magnetic resonance imaging of Ebstein's anomaly: report of two cases.

Among 388 cases of congenital heart disease with magnetic resonance imaging (MRI) from September 1990 to February 1992, we came across two cases of Ebstein's anomaly. They had been previously diagnosed as Ebstein's anomaly by echocardiography and cinecardioangiography. The first case was a three-year-old boy with complex congenital heart disease that included Ebstein's anomaly, a double-outlet right ventricle, pulmonary hypertension, tricuspid regurgitation, mitral regurgitation, a ventricular septal defect and an atrial septal defect. The second was a 13-year-old boy who also had Ebstein's anomaly, but had received a tricuspid valve replacement at the age of five. In Ebstein's anomaly, we found that MRI offers exquisite endocardial and epicardial details. We anticipate that in the future MRI will help to eliminate invasive studies.

Vasopressin in oligohydramnios-induced lung hypoplasia.

Experimentally-induced oligohydramnios (oligo) produces lung hypoplasia. To determine if arginine vasopressin (AVP), a hormone known to decrease fetal lung fluid production, contributes to the pathogenesis of oligo-induced lung hypoplasia, the following experiment was performed. Brattleboro rats were mated to produce litters either with AVP [heterozygotes (HZ)] or without AVP [homozygotes (HO)]. On d 15 of gestation, half of each litter underwent amniocentesis to create persistent oligo. Littermates with intact membranes served as controls. Four groups of fetuses, i.e. 10 HO litters divided into control (44 fetuses) and oligo (25 fetuses), and eight HZ litters divided into control (35 fetuses) and oligo (18 fetuses), were killed at term for measurement of organ weights and biochemical determination of lung development. Significant differences between control and oligo groups were observed for body weight (HO, p = 0.008; HZ, p = 0.03), lung weight (less than 0.001 for both crossings), lung/body weight ratio (less than 0.001 for both), DNA per lung (HO, p = 0.02; HZ, p less than 0.001), and lung dry/wet ratio (HO, p less than 0.001; HZ, p = 0.001). Oligo groups with and without AVP were not found to be different for lung weight (p = 0.217), lung/body weight ratio (p = 0.209), and DNA per lung (p = 0.822). An analysis of variance confirmed the lack of any significant difference of the impact of oligo in the presence or absence of AVP. We conclude that AVP plays no role in the development of oligo-induced lung hypoplasia.

Reevaluation of streptococcal infection in the pathogenesis of Kawasaki disease.

Twenty-five sera from forty-nine children with Kawasaki disease (KD) in the convalescent stage, and 191 sera from controls did not disclose a higher anti-streptolysin O titer; 23 bacterial cultures from the throat swab of KD patients during the acute stage did not show a higher rate of streptococcal isolation. It was therefore concluded that there was no relation between the genesis of KD and direct immediate streptococcal infection.