Three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology: Formulation development and in vitro anticancer activity

Despite recent advances in cancer therapy, many malignant tumors still lack effective treatment and the prognosis is very poor. Paclitaxel is a potential anticancer drug, but its use is limited by the facts that paclitaxel is a P-gp substrate and its aqueous solubility is poor. In this study, three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology was evaluated in vitro as a way of enhancing delivery of paclitaxel. Paclitaxel was incorporated both in biotinylated (BP) and non-biotinylated (LP) PEG-PLA nanoparticles by the interfacial deposition method. Small (mean size approximately 110nm), spherical and slightly negatively charged (-10mV) BP and LP nanoparticles achieving over 90% paclitaxel incorporation were obtained. The successful biotinylation of nanoparticles was confirmed in a novel streptavidin assay. BP nanoparticles were targeted in vitro to brain tumor (glioma) cells (BT4C) by three-step avidin-biotin technology using transferrin as the targeting ligand. The three-step targeting procedure increased the anti-tumoral activity of paclitaxel when compared to the commercial paclitaxel formulation Taxol((R)) and non-targeted BP and LP nanoparticles. These results indicate that the efficacy of paclitaxel against tumor cells can be increased by this three-step targeting method.     

International quit and win 1996: standardized evaluation in selected campaign countries

BACKGROUND: Quit and Win '96 recruited 70,000 smokers in 25 countries. The participants tried to abstain from smoking for at least 4 weeks. All participating countries followed the jointly agreed rules. Half of the countries implemented the campaign nationally and half, regionally. METHODS: A 1-year follow-up study was conducted in the participating countries. The aim of this study was to provide a standardized evaluation based on data from eight European campaign sites. Three measures were used to evaluate the effectiveness of the campaigns. The first measure was the participation rate, which is the proportion of participants among the smoking population targeted in each site. The second measure was a cautious estimate for the continuous 1-year abstinence rate, which is the proportion of abstainers among the follow-up sample regarding all non-respondents as relapsed. Third was the measure of the population impact, which is the efficacy of the intervention multiplied by its reach, where the efficacy equals the abstinence rate and the reach equals the participation rate. RESULTS: The participation rates varied from 0.1 to 2%, being highest in North Karelia, Finland, and Pitka;auranta, Russia. The abstinence rates varied from 12 to 35%, being highest in Hungary, Ukraine, and Russia, where the prevalence of smoking is also relatively high. The population impacts varied from 0.02 to 0.5%, being highest in Pitka;auranta, where both the reach and the efficacy of the Quit and Win were relatively high. CONCLUSIONS: There was great variation in effectiveness, with population impact being affected more by participation rate than abstinence rate. Quit and Win contests are feasible interventions in diverse European populations. To improve the effectiveness, future campaigns should increase the reach of the intervention.     

Endocervical brush cytology. An alternative to endocervical curettage?

The usefulness of an endocervical brush for cytologic sampling was studied in 288 consecutive women attending a colposcopy clinic. One hundred sixty had initial colposcopic examinations with directed biopsies and endocervical curettage (ECC). One hundred twenty-eight had follow-up examinations that included Papanicolaou smears and ECC some time after evaluation and/or treatment for cervical dysplasia. Within an established protocol for the evaluation and management of abnormal Papanicolaou smears, the endocervical brush was compared to ECC. When the combination of colposcopy and cervical conization showed that dysplasia was confined to the endocervix, the endocervical brush was significantly more sensitive than ECC in detecting this endocervical disease (P less than .05). In follow-up evaluations and in patients with unsatisfactory colposcopic examinations, endocervical brush cytology could replace ECC without affecting clinical management. In patients with a satisfactory colposcopic examination, ECC may be required only when endocervical brush cytology is abnormal. Endocervical brush cytology is less costly and painful and could prove to be a reasonable alternative to ECC for the initial evaluation of the endocervix. Endocervical brush cytology shows promise as a safe adjunct to the colposcopic evaluation of pregnant women, whereas ECC is contraindicated in such women.     

Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma

OBJECTIVES: To study the factors determining new recurrences in patients with frequently recurring superficial bladder tumors. METHODS: Of all 205 eligible patients, each received 5 weekly intravesical instillations of mitomycin C (MMC), with the first instillation given perioperatively. This was followed, according to randomization, by BCG instillations alone or by alternating instillations of interferon-alpha and BCG monthly for up to 1 year. Impact of 12 variables on time to first recurrence was retrospectively studied with the Cox multiple hazards regression and Kaplan-Meier analysis. RESULTS: Type of regimen was the most significant factor determining new recurrences, with preceding recurrence rate being the most important prognostic factor. Timing of the first MMC was the third significant predictor in the main multivariate analysis, with more than a two-fold relative risk for a new recurrence if the first MMC instillation was given later than on day 0. CONCLUSION: Preceding recurrence rate, most accurately reflects, in patients with frequently recurring tumors, the inherent risk for new recurrences. This risk can be considerably reduced by use of an effective chemoimmunotherapy regimen, and in addition, by inclusion of an early perioperative chemotherapy instillation in such a regimen.     

Rheological properties of three component creams containing sorbitan monoesters as surfactants

The objectives of the present study were (1) to evaluate the effect of formulation ingredients on the release rate of Ubiquinone from its adsorbing solid compact; and (2) to prepare and evaluate an optimized self-nanoemulsified tablet formulation. A three factor, three-level Box–Behnken design was used for the optimization procedure, with the amounts of copolyvidone (X₁), maltodextrin (X₂) and microcrystalline cellulose (X₃) as the independent variables. The response variable was cumulative percent of Ubiquinone emulsified in 45 min with constraints on weight, flowability index, tensile strength, friability and disintegration time of the dry powdered emulsion and the resultant compact. Based on the experimental design, different Ubiquinone release rates and profiles were obtained. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative percent emulsified in 45 min was Y₆=64.10−12.32X₁−4.36X₂−25.53X₃+6.99X₁X₂+3.97X₁X₃+9.70X₂X₃−8.98X₁²−16.22X₂²+17.10X₃². The optimization model predicted an 85.4% release with X₁, X₂ and X₃ levels of 66.6, 560.1 and 100, respectively. A new formulation was prepared according to these levels. The observed responses were in close agreement with the predicted values of the optimized formulation.     

Genetic and environmental influences on the tracking of body size from birth to early adulthood

OBJECTIVE: This study identified genetic and environmental influences on the tracking of body size from birth to 16 to 18.5 years of age. RESEARCH METHODS AND PROCEDURES: Longitudinal information was collected from a nationally representative sample of Finnish twin adolescents (birth cohorts 1975 to 1979) and their parents through questionnaires mailed when the twins were ages 16 and 18.5 years old. The sample included 702 monozygotic, 724 same-sex dizygotic, and 762 opposite-sex dizygotic sets of twins. The measures used were length, weight, ponderal index (kilograms per cubic meters), and gestational age at birth, and height, weight, and body mass index (kilograms per square meters) at 16 to 18.5 years of age. The changes in genetic and environmental influences on body size from birth to early adulthood were analyzed by quantitative genetic modeling. RESULTS: The twins who had a higher weight or ponderal index at birth were taller and heavier in early adulthood, whereas those who were longer at birth were taller, but not heavier, later in life. Adult height was affected more by the birth size than body mass index. In the genetic modeling analyses, the genetic factors accounting for the variation of body size became more apparent with age, and both genetic and environmental influences on stature had a sizable carry-over effect from birth to late adolescence, whereas for relative weight, the influences were more age-specific. DISCUSSION: The genetic and environmental architecture of body size changes from birth to adulthood. Even in monozygotic twins who share their genetic background, the initially larger twin tended to remain larger, demonstrating the long-lasting effects of fetal environment on final body size.     

Genetic risk determines the emergence of diabetes-associated autoantibodies in young children

Timing of onset of autoimmunity is a prerequisite for unmasking triggers and pathogenesis of type 1 diabetes. We followed 4,590 consecutive newborns with 8 or 3% HLA-DQB1 conferred risk for type 1 diabetes at 3-, 6-, or 12-month intervals up to 5.5 years of age. Islet cell autoantibodies (ICAs) and, in the 137 children with ICAs, insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and IA-2 protein autoantibodies (IA-2As) were measured. Children with high genetic risk developed ICAs more often than those with moderate risk (log-rank P = 0.0015); 85 and 91% remained ICA negative by 5 years of age, respectively. The time of appearance of biochemical autoantibodies was then compared with the appearance of ICAs. IAAs and GADAs emerged usually before ICAs (means -1.8 and -1.5 months, respectively) and IA-2As after ICAs (mean 2.0 months). Ninety-five percent of all IAAs, GADAs, and IA-2As seroconversions occurred in a cluster (-12 to 8 months) around the ICA seroconversion. We conclude that diabetes-associated autoantibodies emerged in children with predisposing HLA-DQB1 alleles after 3 months of age at a constant tempo, determined by the genetic risk level, usually in the order of IAA, GADA, ICA, and IA-2A. Seroconversion to multiple autoantibody positivity usually occurred tightly clustered in time.     

Phenotypic spectrum of Salla disease, a free sialic acid storage disorder

Salla disease (MIM 269920) represents the mildest phenotype among recessively inherited lysosomal-free sialic acid storage disorders. Although the vast majority of Salla disease patients in Finland share the same founder mutation, R39C in the SLC17A5 gene, there still is a wide clinical variation among mentally retarded, ataxic patients. We evaluated neurologic and neurocognitive findings of Salla disease in a cross-sectional study of 41 Finnish patients who were 11 months to 63 years of age (median = 19.5 years). The phenotype of Salla disease could be classified into two main categories. The majority of patients (90%) had so-called conventional phenotype, including a subgroup of seven patients with relatively mild symptoms. All but two patients with conventional phenotype were homozygous for the Finnish founder mutation. Four severely disabled, profoundly mentally retarded patients, 15-28 years of age, clearly could be clinically delineated as a separate group, likely reflecting the underlying compound heterozygous genotype. A typical developmental pattern could be outlined in the conventional type of the disease, emphasizing a strong motor handicap in Salla disease. The cognitive profile consisted of better verbal ability, especially speech comprehension, compared with nonverbal functioning in all patients. Our results indicate a partial genotype-phenotype correlation, although factors other than the molecular background are also involved in the phenotypic manifestation of Salla disease.