Gene therapy of liver cancer: an update

Liver cancer is one of the most important health problems worldwide, due to its high incidence and remarkable resistance to conventional treatments. Hepatocellular carcinoma (HCC) accounts for more than 80% of the primary liver cancers. The burden of HCC in Africa is remarkable because some of the major etiologic factors, such as chronic hepatitis B infection and exposure to mycotoxins are particularly frequent in this continent. Besides the urgent need for prevention campaigns, new therapeutic options are needed to improve the management of HCC patients. Gene therapy (GT) is an experimental discipline that is rapidly evolving to solve the important obstacles identified in early clinical trials. Despite the particular difficulties inherent in the transfer of genes into tumors, cancer is still one of the most frequent applications of GT. Recent technical and scientific advances in gene therapy and combined cell and gene therapy, together with new radiotherapy techniques and immunotherapy in patients with HCC have opened new possibilities in this field. Here we summarize the actual trends in GT approaches for the treatment of HCC.     

Genital folliculo‐sebaceous cystic hamartoma: A claim of the stroma as a clue in the diagnosis of proliferations with follicular differentiation

Folliculo‐sebaceous hamartomas comprise a series of entities whose boundaries are imprecise. We present the clinical case of a folliculo‐sebaceous cystic hamartoma of genital localization where the diagnosis was established based on the epithelial proliferation, but mostly, on the characteristic stroma. Because this lesion lacked of the cystic component, we mention the most frequent differential diagnoses and review the literature of the few cases published on this infrequent localization.     

The involvement of the renin-angiotensin system gene polymorphisms in coronary heart disease

INTRODUCTION AND OBJECTIVES: Previous studies angiotensin-converting enzyme gene insertion/deletion polymorphism ACE (I/D), angiotensinogen gene polymorphism, and angiotensin II AT1 receptor polymorphism in relation to coronary heart disease controversial results. This study was designed to analyze the association between these gene polymorphisms and the first coronary event in individuals residing on Grand Canary Island, Spain. PATIENTS AND METHOD: Case-control study. Case subjects (n = 304) were recruited at the first coronary event; age-matched controls (n = 315) were randomly selected from the Grand Canary population. Participants were examined for the usual risk factors. Blood samples were obtained for biochemical analyses and DNA extraction. Genotyping was performed by PCR and restriction analysis. RESULTS: Neither ACE (I/D) nor AT1 receptor polymorphism was associated with coronary heart disease, whereas the frequency distribution of AGT M235T genotypes among patients and control subjects (TT: 29% and 19%; MT: 48% and 50%; MM: 22% and 31%, respectively) was statistically different (p = 0.003). Multiple logistic regression analysis identified the TT genotype of the angiotensinogen gene (OR = 1.9; 95% CI 1.1-3.4), diabetes (OR = 4.4; 95% CI 2.0-9.4) and hypertension (OR = 2.1; 95% CI 1.3-3.3) as risk factors predicting the coronary event. CONCLUSIONS: Our results provide no evidence of an association between ACE (I/D) or AT1 receptor polymorphism and coronary heart disease. However, homozygosity for the T allele of the angiotensinogen gene, diabetes and hypertension independently place individuals at higher risk of experiencing a coronary event on Grand Canary Island.     

The effects of nisoldipine on the total ischaemic burden: the results of the ROCKET study

This study was designed to examine the effects of nisoldipine(relative to placebo), a new dihydropyridine calcium entry blockingagent, in the treatment of silent ischaemia in conventionaldoses. A total of 409 patients with proven coronary artery diseasewere screened and of this 64 had at least six episodes or atotal duration of 30 mm of ST segment depression (1 mm lastingat least 1 min) over 48 h. Fifty-two patients ultimately completeda randomized double-blind cross-over study comparing nisoldipine5 mg twice a day, nisoldipine 10 mg daily and placebo. There was a reduction in the ST segment integral and numberof episodes of ST segment depression when compared to placeboon treatment with nisoldipine 5 mg twice a day and nisoldipine10 mg daily. However, the confidence limits were wide and crossedthe no-treatment effect line. In addition, the nisoldipine dosesneither affected the circadian distribution of ischaemic episodesnor caused an alteration of the workload achieved either atpeak exercise or at 1 mm ST segment depression measured 24 hafter nidoldipine 10 mg or 12 h after nisoldipine 5 mg. We conclude that frequent silent ischaemia in patients withproven coronary artery disease is relatively uncommon, it accountsfor approximately 16% of patients with positive exercise. Inthese patients nisoldipine, given as 5mg twice a day and 10mg daily, showed no significant therapeutic effects, eitheron the frequency or severity of silent ischaemia. New formulationsof slow release nisoldipine are consequently being developedso that a fuller 24 h therapeutic profile may be obtained.     

Doppler haemodynamic assessment of clinically and echocardiographically normal mitral and aortic Allcarbon valve prostheses

Doppler echocardiographic characteristics of normally functioningAllcarbon prostheses were studied in 149 consecutive patientswith 157 valves in the mitral (n=73) and aortic (n=84) positionswhose function was considered normal by clinical and echocardiographicevaluation. In the mitral position, the mean gradient and theeffective mitral orifice area were not significantly differentin either the 25-mm or the 31-mm size valves (from 5±1to 4±1 mmHg and from 2.2±0.6 to 2.8±0.9cm², respectively; P=ns for both). Conversely, peak gradientwas significantly and inversely correlated to actual orificearea (r=–0.70; P<0.0006), decreasing from 15±3mmHg in the 25-mm size valve to 9±1 mmHg in the 31-mmsize. In the aortic position, the mean gradient was 29±8 mmHgin the 19-mm size valve; it decreased to 8±2 mmHg inthe 29-mm size. Effective prosthetic aortic valve area, calculatedusing the continuity equation, ranged between 0.9±0.1cm² for the 19-mm size valve to 4.1±0.7 cm² for the 29-mmsize. By analysis of variance, effective prosthetic aortic valvearea differentiated various valve sizes (F=25.3; P<0.0001)better than peak (F=5.34; P=0.012) or mean (F=4.34; P=0.0052)gradients alone, and it correlated better with actual orificearea (r=0.89, r=–0.70 and r=–0.65, respectively).This study provides the normal range for Doppler haemodynamiccharacteristics of the various sizes of the Allcarbon valvein the mitral and aortic positions so that prosthetic malfunctioncan be identified.     

Cyanobacterium producing cylindrospermopsin cause histopathological changes at environmentally relevant concentrations in subchronically exposed tilapia (Oreochromis niloticus)

The acute toxicity of cylindrospermopsin (CYN) has been established in rodents, based on diverse intraperitoneal an oral exposure studies and more recently in fish. But no data have been reported in fish after subchronic exposure to cyanobacterial cells containing this cyanotoxin, so far. In this work, tilapia (Oreochromis niloticus) were exposed by immersion to lyophilized Aphanizomenon ovalisporum cells added to the aquaria using two concentration levels of CYN (10 or 100 μg CYN L^?1) and deoxy‐cylindrospermopsin (deoxy‐CYN) (0.46 or 4.6 μg deoxy‐CYN L^?1), during two different exposure times: 7 or 14 d. This is the first study showing damage in the liver, kidney, hearth, intestines, and gills of tilapia after subchronic exposure to cyanobacterial cells at environmental relevant concentrations. The major histological changes observed were degenerative processes and steatosis in the liver, membranous glomerulopathy in the kidney, myofibrolysis and edema in the heart, necrotic enteritis in the gastrointestinal tract, and hyperemic processes in gill lamellae and microhemorrhages. Moreover, these histopathological findings confirm that the extent of damage is related to the CYN concentration and length of exposure. Results from the morphometric study indicated that the average of nuclear diameter of hepatocytes and cross‐sections of proximal and distal convoluted tubules are useful to evaluate the damage induced by CYN in the main targets of toxicity. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 261–277, 2015.     

Antioxidant status and glutathione metabolism in peripheral blood mononuclear cells from patients with chronic hepatitis C

BACKGROUND/AIMS: Oxidative stress could play a role in the pathogenesis of hepatitis C virus infection. We investigated the oxidant/antioxidant status in peripheral blood mononuclear cells from patients with chronic hepatitis C and controls. METHODS/RESULTS: Lipid peroxidation products and superoxide dismutase activity in peripheral blood mononuclear cells were higher in chronic hepatitis C patients than in healthy subjects while glutathione S-transferase activity was reduced in patients as compared to controls. Catalase, glutathione peroxidase and glutathione reductase were similar in chronic hepatitis C and normal individuals. No statistically significant differences were found between patients and controls with regard to glutathione levels in peripheral blood mononuclear cells, but 35% of patients with chronic hepatitis C showed values of glutathione and oxidized glutathione which were below and above, respectively, the limits of normal controls. Finally, the glutathione synthetic capacity of the cytosol of peripheral blood mononuclear cells was significantly higher in patients than in controls, indicating increased glutathione turnover in lymphocytes from patients with chronic hepatitis C. CONCLUSIONS: Oxidative stress is observed in peripheral blood mononuclear cells from chronic hepatitis C patients. This process might alter lymphocyte function and facilitate the chronicity of the infection.