Acetylsalicylic acid and salicylic acid decrease tumor cell viability and glucose metabolism modulating 6-phosphofructo-1-kinase structure and activity

The common observation that cancer cells present higher glycolytic rates when compared to control cells leads to the proposal of glycolysis as a potential target for the development of anti-tumoral agents. Anti-inflammatory drugs, such as acetylsalicylic acid (ASA) and salicylic acid (SA), present anti-tumoral properties, inducing apoptosis and altering tumor glucose utilization. The present work aims at evaluating whether ASA could directly decrease cell glycolysis through inhibition of the major regulatory enzyme within this pathway, 6-phosphofructo-1-kinase (PFK). We show that ASA and SA inhibit purified PFK in a dose-dependent manner, and that this inhibition occurs due to the modulation of the enzyme quaternary structure. ASA and SA promote the dissociation of the enzyme active tetramers into quite inactive dimers, a common regulatory mechanism of this enzyme. The inhibitory effects of ASA and SA on PFK are fully reversible and can be prevented or reverted by the binding of the enzyme to the actin filaments. Both drugs are also able to decrease glucose consumption by human breast cancer cell line MCF-7, as well as its viability, which decrease parallelly to the inhibition of PFK on these cells. In the end, we demonstrate the ability of ASA and SA to directly modulate an important regulatory intracellular enzyme, and propose that this is one of their mechanisms promoting anti-tumoral effects.     

Alternative antibody for the detection of CA125 antigen: a European multicenter study for the evaluation of the analytical and clinical performance of the Access OV Monitor assay on the UniCel Dxl 800 Immunoassay System

BACKGROUND: Cancer antigen CA125 is known as a valuable marker for the management of ovarian cancer. METHODS: The analytical and clinical performance of the Access OV Monitor Immunoassay System (Beckman Coulter) was evaluated at five different European sites and compared with a reference system, defined as CA125 on the Elecsys System (Roche Diagnostics). RESULTS: Total imprecision (% CV) of the OV Monitor ranged between 3.1% and 8.8%, and inter-laboratory reproducibility between 4.7% and 5.0%. Linearity upon dilution showed a mean recovery of 100% (SD + 8.1%). Endogenous interferents had no influence on OV Monitor levels (mean recoveries: hemoglobin 107%, bilirubin 103%, triglycerides 103%). There was no high-dose hook effect up to 27,193 kU/L. Clinical performance investigated in sera from 1811 individuals showed a good correlation between the Access OV Monitor and Elecsys CA125 (R = 0.982, slope = 0.921, intercept = +1.951). OV Monitor serum levels were low in healthy individuals (n = 267, median = 9.7 kU/L, 95th percentile = 30.8 kU/L), higher in individuals with various benign diseases (n = 549, medians = 10.9-16.4 kU/L, 95th percentiles = 44.2-355 kU/L) and even higher in individuals suffering from various cancers (n = 995, medians = 12.4-445 kU/L; 95th percentiles = 53.4-4664 kU/L). Optimal diagnostic accuracy for cancer detection against the relevant benign control group by the OV Monitor was found for ovarian cancer [area under the curve (AUC) 0.898]. Results for the reference CA125 assay were comparable (AUC 0.899). CONCLUSIONS: The Access OV Monitor provides very good methodological characteristics and demonstrates an excellent analytical and clinical correlation with Elecsys CA125. The best diagnostic accuracy for the OV Monitor was found in ovarian cancer. Our results also suggest a clinical value of the OV Monitor in other cancers.     

Glial and axonal perikaryal coverage and somatic spines in the posterodorsal medial amygdala of male and cycling female rats

The posterodorsal medial amygdala (MePD) is a sex‐steroid‐sensitive area that modulates reproductive behavior in rats. The volume of the neuronal cell body, density of dendritic spines, and glial fibrillary acidic protein immunoreactivity are sexually dimorphic or affected by gonadal hormones in the MePD. Here we add new data to this panorama and describe the ultrastructure of the glial and axonal coverage of the perikaryal membrane and the somatic spines in the MePD of males and cycling females (in diestrus, early proestrus, late proestrus, and estrus). Transmission electron microscopy data (mean values from seven to 11 neurons per rat, five or six animals per group) showed that the rat MePD has most of the perikaryal membrane covered by glial processes and a relatively large amount (up to 40%) of axonal processes contacting the neuronal cell body. No statistically significant difference was found between groups for these somatic coverages (P > 0.5). However, the density of somatic spines along the length of the perikaryal membrane was higher in the late proestrus than in estrus (P < 0.05), and somatic spines in early and late proestrus showed variable shapes with stubby/wide, thin, mushroom‐like, ramified, transitional or atypical aspects. These findings add to the rapid adjustable synaptic changes in the MePD and in the integrated neural circuits that control neuroendocrine secretion and the hormonally modulated timely display of social behaviors in rats. J. Comp. Neurol. 523:2127–2137, 2015. © 2015 Wiley Periodicals, Inc.     

Asymptomatic sacroiliitis detected by magnetic resonance enterography in patients with Crohn's disease: prevalence,association with clinical data,and reliability among radiologists in a multicenter study of adult and pediatric population

Clinical Rheumatology - Patients with Crohn's disease (CD) usually undergo magnetic resonance enterography (MRE) for evaluating small bowel involvement. Musculoskeletal symptoms are the most...     

Isoniazid-related fulminant hepatic failure in a child: assessment of the native liver's early regeneration after auxiliary partial orthotopic liver transplantation

Abstract We report the first case of auxiliary partial orthotopic liver transplantation (APOLT) in a patient with isoniazid (INH)-related fulminant hepatic failure (FHF) with the aim to determine the ability of the native liver (NL) to recover after this particular toxic event. A 10-year-old boy with INH-related FHF underwent APOLT after left hepatectomy on the NL. Neurological status and liver function rapidly improved, but, on postoperative day 22, urgent re-transplantation was needed for graft-hepatic artery thrombosis (HAT) and the NL's incapacity to sustain adequate liver function. Histological examination of the NL showed signs evident of its regeneration, however. In conclusion, though we faced the clinical failure of the NL functionally to sustain the patient in the presence of the graft HAT 3, weeks after APOLT, such a failure may be interpreted as time related. In fact, the histological picture in this particular case may suggest the potential for NL recovery after INH-related FHF     

Venous and arterial thrombosis in rat models: dissociation of the antithrombotic effects of glycosaminoglycans.

Fucosylated chondroitin sulfate is a glycosaminoglycan from sea cucumber, made up of alternating beta-D-glucuronic acid and N-acetyl-beta-D-galactosamine units, like mammalian chondroitin sulfate. But the beta-D-glucuronic acid residues have branches of sulfated fucose, which confer high anticoagulant and antithrombotic properties on this compound. We have now compared the anticoagulant, bleeding and antithrombotic effects of this fucosylated chondroitin sulfate and its carboxyl-reduced derivative. Both compounds have similar anticoagulant action, mostly due to acceleration of thrombin inhibition in the presence of heparin cofactor II. The native glycosaminoglycan shows a correlation among anticoagulant, bleeding and antithrombotic effects. Inhibition of thrombosis in an arterio-venous shunt occurs at low doses, which are almost ineffective in modifying the anticoagulant activity of plasma. In a venous experimental model, on the contrary, antithrombotic activity requires high doses and occurs concomitantly with an increase in the anticoagulant activity of plasma. The action of fucosylated chondroitin sulfate on thrombosis is apparently unrelated to its effect on platelet aggregation. The carboxyl-reduced derivative of fucosylated chondroitin sulfate prevented thrombosis in the arterio-venous shunt, but not in the venous experimental model. This derivative did not increase bleeding, in spite of its potent anticoagulant activity. Therefore, our results reveal a dissociation of the anticoagulant, bleeding and antithrombotic effects of the glycosaminoglycan. Furthermore, we demonstrate that a polysaccharide may be a potent inhibitor of one type of thrombotic episode, but inactive on another. We propose that the different effects of fucosylated chondroitin sulfate and its carboxyl-reduced derivative on venous thrombosis may be related to adherence of the glycosaminoglycan to the vessel wall.     

Pediatric HBsAg chronic liver disease and adult asymptomatic carrier status: two stages of the same entity

Unlike adults (greater than 60% of cases), it is rare to find the chronic hepatitis B virus (HBV) carrier status with normal transaminases among children. The aim of this study was to investigate whether this status would depend on the duration of HBV infection, that is, whether chronic hepatitis in childhood would lead to the asymptomatic carrier status in later life. We reexamined all of our patients with chronic HBV infection of greater than 10 years' duration and with histologically documented chronic hepatitis during childhood. This was a group of 36 adolescents and young adults. All subjects were screened for tumor using alpha-fetoprotein assay and hepatic ultrasound. Eight patients with cirrhosis underwent esophageal fiberoptic endoscopy. All patients were in good general condition, with no clinical signs of liver failure. Only two patients had abnormal transaminase levels, both of whom had evidence of delta infection. All but one patient became anti-HBe positive. Five cases had HBsAg clearance. (Seventy-one percent of patients were HBeAg positive and 14% anti-HBe positive at the onset of the disease.) Hepatic ultrasound revealed no tumors in any of the subjects, and fiberoptic endoscopy demonstrated no esophageal varices. This study suggests that (a) chronic hepatitis and asymptomatic carrier status may be subsequent stages of the B virus infection; and (b) chronic hepatitis in childhood is generally benign and may evolve into an asymptomatic carrier status. The main problem with the chronic carrier status is probably the increased risk of hepatocellular carcinoma.     

Hyperthyroid-induced chorea in an adolescent girl.

Hyperthyroidism is invariably accompanied by nervous system dysfunctions. Irritability, emotional lability and hyperkinesia are the signs and symptoms most frequently observed. Chorea or choreoathetosis are only rarely associated with hyperthyroidism. It is the purpose of this work to describe the case of a young girl in whom chorea was the main manifestation of thyrotoxicosis. The chorea receded and disappeared as the patient became euthyroid. Hyperthyroidism, therefore, is to be considered an unusual cause of chorea and every patient with choreiform movements should be examined also for thyroid function.