SGI-110: DNA Methyltransferase Inhibitor Oncolytic.

SGI-110 is a second-generation hypomethylating prodrug whose active metabolite is the well-characterized drug decitabine. This novel compound is an oligonucleotide consisting of decitabine linked through a phosphodiester bond to the endogenous nucleoside deoxyguanosine. The dinucleotide configuration provides protection from drug clearance by deamination, while maintaining at least equivalent effects on gene-specific and global hypomethylation both in vitro and in animal model systems. This agent is currently being tested in phase I and II clinical trials in humans and has been demonstrated to be safe and well tolerated as a single agent, with evidence of promising activity in heavily pretreated (including currently FDA approved hypomethylating drugs) myelodysplastic syndrome and acute myeloid leukemia patients. Ongoing trials are also open in platinum-resistant ovarian cancer and hepatocellular carcinoma.

Plasma and cerebrospinal fluid pharmacokinetics of MP470 in non-human primates.

PURPOSE: MP470 is a multi-targeted tyrosine kinase inhibitor with potent activity against mutant c-Kit, PDGFRα, Flt3, c-Met and c-Ret that is being evaluated as an anticancer agent. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of MP470 were studied in a non-human primate model that is highly predictive of CSF penetration in humans. METHODS: Oral MP470, 300 mg, was administered to four non-human primates. Serial samples of blood were collected from four animals and CSF samples from three animals for pharmacokinetic studies. Plasma and CSF concentrations were measured using an LC-MS/MS assay. Both model-independent and model-dependent methods were used to analyze the pharmacokinetic data. RESULTS: Following a one-time oral dose of 300 mg, the MP470 plasma area under the curve (AUC) was 1,690 ± 821 nM h (mean ± SD). The half-life of MP470 in the plasma was 11.0 ± 3.4 h. There was no measurable MP470 in the CSF. CONCLUSIONS: Although CSF penetration is minimal, MP470 has demonstrated potent activity against cancer cell lines in vitro and in vivo, and further clinical investigation is warranted.

Epidemiological features of human immunodeficiency virus infection in rural area of western India.

OBJECTIVES: To investigate epidemiological features of human immunodeficiency virus (HIV) infection first time in rural areas of Western India, Maharashtra. METHODS: Cross-sectional prospective study with relevant investigations of 290 patients, 181 males and 109 females of age group up to 60 years, screened by two methods, Tridot or Combiads and Eliza test. Criteria were repeated respiratory infections, pulmonary tuberculosis with recurrence or relapse in spite of adequate multidrug therapy (MDT), chronic skin infections, venereal diseases, pyrexia of unknown origin, weight loss, generalised lymphadenopathy and wives of all HIV positive persons. RESULTS: 51 persons were found HIV +ve (17.5% prevalence rate), 57% of the wives of HIV +ve were infected. 42% of the patients of tuberculosis with recurrence or repeated respiratory infection and 50% of patients presenting only with weight loss more than 10% of body weight were positive. Heterosexual transmission was predominant, middle income group, male dominance and age group between 21 to 40 was infected most. The most common superinfection in 28 acquired immunodeficiency syndromes (AIDS) cases was Mycobacterium tuberculosis (100%) responded to MDT but after recurrence there was progressive failure of response to therapy. Five patients of AIDS had scabies which failed to respond. Out of 9 AIDS patients, 5 had chronic amoebic dysentry which also did not respond. Retinal examination showed cotton wool feather shaped spots in four AIDS cases and in one asymptomatic HIV +ve person. These spots went on increasing as diseases progressed. Time interval between detection of AIDS patients and death was short (12 to 18 months). CONCLUSIONS: HIV infection is spreading in rural area of Western India so rapidly that it will seriously jeopardize primary health care. Non-responding infections like scabies and amoebic dysentry may be presenting symptoms in AIDS in additions to resistant tuberculosis.

Placental alkaline phosphatase in patients with seminoma measured by ELISA as compared to RIA.

Placental alkaline phosphatase (PLAP) has been shown to be a reliable tumor marker in the management of patients with seminoma. Radioimmunoassay (RIA) and Enzyme linked immunoassay (ELISA) procedures were compared for PLAP levels in serum of seminoma patients. The statistical analysis showed excellent correlationship between the two. It is evident from the results that performance of ELISA in terms of sensitivity specificity, precision, accuracy and reproducibility is equivalent to or better than RIA.

Crossflow microfiltration of yeast suspensions in tubular filters.

Crossflow microfiltration experiments were performed on yeast suspensions through 0.2-microns pore size ceramic and polypropylene tubes at various operating conditions. The initial transient flux decline follows dead-end filtration theory, with the membrane resistance determined from the initial flux and the specific cake resistance determined from the rate of flux decline due to cake buildup. For long times, the observed fluxes reach steady or nearly steady values, presumably as a result of the cake growth being arrested by the shear exerted at its surface. The steady-state fluxes increase with increasing shear rate and decreasing feed concentration, and they are nearly independent of transmembrane pressure. The steady-state fluxes for unwashed yeast in deionized water or fermentation media are typically 2-4 times lower than those predicted by a model based on the properties of nonadhesive, rigid spheres undergoing shear-induced back-diffusion. In contrast, the steady-state fluxes observed for washed yeast cells in deionized water are only 10-30% below the predicted values. The washed yeast cells also exhibited specific cake resistances that are an order of magnitude lower than those for the unwashed yeast. The differences are due to the presence of extracellular proteins and other macromolecules in the unwashed yeast suspensions. These biopolymers cause higher cell adhesion and resistance in the cake layer, so that the cells at the top edge are not free to diffuse away. This is manifested as a concentration jump from the edge of the cake layer to the sheared suspension adjacent to it.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical significance of serum spermine in breast cancer.

The diagnostic significance of three polyamines (putrescine, spermidine and spermine), of carcinoembryonic antigen and of phosphoglucose isomerase have been compared in sera of patients with breast cancer or benign breast disease and normal age matched controls. The results of the study indicate that the performance of spermine was more striking than that of any of the other markers. The estimation of spermine may prove to be a valuable parameter not only in detection but also in prediction of recurrence of the disease.

Terminal deoxynucleotidyl transferase in acute leukemias by direct immunofluorescence.

TdT (terminal deoxynucleotidyl transferase) can be detected by radio enzymatic assay, biochemical assay in cell extracts, serum or plasma, and intracellularly in the smear by indirect immunofluorescent methods. The IgG fraction of anti-TdT serum is conjugated with fluoresceinisothiocyanate and used directly on the cytospin smears of methanol fixed bone marrow/blood smears. The mice thymocytes and peripheral mononuclear cells of healthy donors were used as positive and negative controls, respectively, for TdT. 64% of our cases of ALL were found to be TdT+. The lymphoblasts of L1 morphology (FAB classification) were more frequently positive for TdT as compared to blasts with L2 morphology. 71% of our cALLa positive blasts in acute lymphoblastic leukemias were TdT+ve as compared to 58% of T-ALL blasts. 75% of PAS positive ALL cases were positive for TdT as well. Only 57% of the cases when acid phosphatase showed unipolar positivity (T type) were positive for TdT. 12% of cases with acute myeloid leukemia (6/47) were TdT+ve and 33% of CML in blastic crisis had TdT+ve blasts. Biochemical assay and IF assay for TdT were in good correlation in our study.