HIV-1 entry inhibitors: classes, applications and factors affecting potency

Antiviral agents targeting human immunodeficiency virus type-1 (HIV-1) attachment, co-receptor engagement and fusion, collectively referred to as entry inhibitors, are emerging as promising therapeutic agents in the treatment of HIV-1 infection. Viral evolution and concomitant emergence of resistant strains will continue to be an important consideration in the development of any new therapeutic against HIV-1. However, unique challenges facing the development of entry inhibitors center around the highly variable and flexible nature of the HIV-1 envelope protein (Env). For example, the evolution of Env during the course of HIV-1 infection increases the efficiency of Env-CCR5 interactions, which consequently increases Env-mediated fusogenicity and decreases sensitivity to entry inhibitors. This points to a relationship between co-receptor interactions and fusogenicity that merits further consideration in the design of HIV-1 entry inhibitors. It also underscores the importance of considering the biological properties of late-emerging HIV-1 variants in the design of new therapeutics. This review examines the various entry inhibitors that are undergoing preclinical or clinical testing or which are in the early stages of clinical use, their applications in a clinical setting and possible factors that may affect potency against HIV-1.     

Expression and prognostic value of the Ki-67 in Wilms’ tumor: experience with 48 cases

Purpose  

Ki-67, tumor proliferation marker, is an important prognostic factor in a variety of cancers. In the present study, we investigated the expression and the prognostic value of Ki-67 in nephroblastoma.     

Potential beneficial role of sevelamer hydrochloride in diabetic retinopathy

Patients with chronic kidney disease (CKD) experience co-morbid illnesses, including cardiovascular disease and retinopathy. Sevelamer hydrochloride (Renagel®); a non-calcium phosphate binder reduces coronary artery and aortic calcification as compared to calcium containing phosphate binders and additionally effects inflammatory biomarkers such as C-reactive protein (CRP), and lowers LDL cholesterol in patients with CKD. Since retinopathy is proven to be associated with increased coronary calcification, shared pathophysiological processes may contribute to both microvascular and macrovascular disease. We here suggest three different mechanisms of possible sevelamer’s influence on the retinopathy: (1) by direct effect on the microvasculature through lowering CRP and LDL, involved in endothelial dysfunction and atherogenesis, (2) indirectly by attenuation of vascular calcification of aorta and carotid internal artery, it reduces ischaemia and improves circulation in the opthalmic artery and hence postponing retinopathy, (3) through hypertension by reducing atherosclerosis and calcification of carotid arteries, sevelamer decreases stiffness and intima-media wall thickness, therefore lowering blood pressure, which is well known to increase progression of diabetic retinopathy. So far no studies have yet been published on the direct influence of sevelamer on the retinopathy which we believe has good theoretical background. With its combined macrovascular and microvascular effect, sevelamer could potentially postpone and/or decrease retinopathy in diabetic patients with hypertension, and that are on hemodialysis or even predialysis patients.     

The value of preoperative intracavitary radiation in uterine carcinoma

The analysis comprised 240 uterine carcinomas: 145 carcinomas of the cervix and 95 carcinomas of the corpus uteri. Preoperatively 100 patients--57 with the carcinoma of the cervix and 43 with the carcinoma of the uterine body--were radiated with Co60 intracavitary. In the first stage of the carcinoma of the cervix a five-year survival in primarily operated patients amounted to 74.30% and in the group of preoperatively intracavitary radiated patients to 83%. In patients with the stage I carcinoma of the corpus uteri a five-year survival proved to be 69.57% if primarily operated and 93.75% if preoperatively radiated. Local relapses were recorded in 33 patients surgically treated for carcinoma of the uterine cervix and in 9 patients surgically treated for the carcinoma of the uterine body. In both these localizations the relapses were more frequent in the group primarily operated patients: in patients with the primarily operated carcinoma of the cervix the relapses occurred in 20.69% and in preoperatively radiated patients in 3.4% of cases. The same observations were recorded in the carcinoma of the corpus uteri (11.51% : 6.97%). This means that the relapses were six times as frequent in patients with the primarily operated carcinoma of the uterine cervix and about 1.65 times as frequent in those with the primarily operated carcinoma of the corpus uteri as in intracavitary radiated patients.     

Primary malignant melanoma of the stomach

We report a 54-year-old patient with a complaint of weakness, abdominal pain and weight loss. During the clinical examination a palpable tumor resistance in the abdomen was found as well as iron deficiency anemia. Gastroscopy showed an exulcerated, dark brown, fungiform tumor about 4 cm in diameter at the great curve of stomach. Endoscopic biopsy revealed the diagnosis of malignant melanoma by demonstrating the presence of melanin containing tumor cells in gastric mucosa. The patient underwent subtotal gastrectomy, appendectomy and splenectomy. The diagnosis of gastric melanoma with regional lymph node metastases, as well as metastases in appendix adjacent tissue was confirmed by histology and immunohistochemistry. In three years follow up period patient developed cerebral and retroauricular subcutaneous metastases that were treated by surgery, adjuvant chemotherapy and radiotherapy. Finally, an explorative laparatomy was revealed advanced intraabdominal tumor dissemination with dark pigmented ascites. Concerning that all available diagnostic procedures failed to prove other site of melanoma, presented case was considered as primary gastric melanoma as a possible rare site of tumor.     

Determination of peracetic acid and hydrogen peroxide in a preparation

Iodometric and permanganometric titrations were used for determination of peracetic acid and hydrogen peroxide (H2O2) in the mixture. Two procedures were described and compared. Titrations could be done in only one vessel, in the same reaction mixture, when iodometric titration of peracetic acid was continued after the permanganometric titration of H2O2, (procedure A). Peracetic acid and H2O2, as oxidizing agents, reacted with potassium iodide in an acid medium, evolving iodine. This reaction was used for the quantitative iodometric determination of total peroxide in procedure B. H2O2 reacted with potassium permanganate in acid medium, but peracetic acid did not react under the same conditions. That made possible the selective permanganometric determination of H2O2 in the presence of peracetic acid. The procedure B was performed in two titration vessels (KV = 3.4% for peracetic acid, 0.6% for H2O2). The procedure A for iodometric determination of peracetic acid in one titration vessel after permanganometric titration of H2O2 was recommended (KV = 2.5% for peracetic acid, 0.45% for H2O2).     

The consequences of insulin-like growth factors/receptors dysfunction in lung cancer

The aim of this study was to investigate the consequences of insulin-like growth factors (IGF) and IGF receptor dysfunction in lung carcinomas. A correlation between increased expression (at mRNA and protein levels) for IGF-1 and IGF-1R and decreased apoptosis were found in large-cell carcinomas and adenocarcinomas. In 40% of informative adenocarcinomas expressing the highest values of IGF-2 and Ki-67 proteins, M6P/IGF-2R gene had LOH at one allele and a mutation in another allele. All four squamous cell carcinoma samples expressed LOH/mutation in the M6P/IGF-2R gene. The alphaIR3 strongly diminished proliferation and increased apoptosis in cultures established from squamous cell carcinomas overexpressing IGF-2 and IGF-1R. Telomerase activity was assessed in four squamous cell carcinomas. Cell treatment with IGF-1 increased telomerase activity. The opposite was observed when the cells were treated with alphaIR3, which inhibits the activity of IGF-1 receptors. Our findings suggest that disruption of the IGF/IGF receptors axis is involved in lung cancer formation.