Multimodal imaging for a theranostic approach in a murine model of B-cell lymphoma with engineered nanoparticles

Nanoparticles (NPs) are a promising tool for in vivo multimodality imaging and theranostic applications. Hyaluronic acid (HA)-based NPs have numerous active groups that make them ideal as tumor-targeted carriers. The B-lymphoma neoplastic cells express on their surfaces a clone-specific immunoglobulin receptor (Ig-BCR). The peptide A20-36 (pA20-36) selectively binds to the Ig-BCR of A20 lymphoma cells. In this work, we demonstrated the ability of core-shell chitosan-HA-NPs decorated with pA20-36 to specifically target A20 cells and reduce the tumor burden in a murine xenograft model. We monitored tumor growth using high-frequency ultrasonography and demonstrated targeting specificity and kinetics of the NPs via in vivo fluorescent reflectance imaging. This result was also confirmed by ex vivo magnetic resonance imaging and confocal microscopy. In conclusion, we demonstrated the ability of NPs loaded with fluorescent and paramagnetic tracers to act as multimodal imaging contrast agents and hence as a non-toxic, highly specific theranostic system.     

Dissolution and Translational Modeling Strategies Enabling Patient-Centric Drug Product Development: the M-CERSI Workshop Summary Report

On May 15th–17th, 2017, the US FDA and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) held a workshop at the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI), to discuss the role of dissolution testing and translational modeling and simulation in enabling patient-centric solid oral drug product development. This 3-day event was attended by scientists from regulatory agencies, pharmaceutical companies, and academia. The workshop included podium presentations followed by breakout session discussions. The first day of the meeting focused on the challenges in dissolution method development and the role of dissolution testing throughout drug product development. On the second day, approaches to establish a link between in vitro testing and in vivo drug product performance (e.g., systemic exposure) were presented. Overall success rates and challenges in establishing IVIVCs via traditional and modern physiologically based pharmacokinetic (PBPK) modeling and simulation approaches were discussed. Day 3 provided an opportunity to discuss the expectations for establishing clinically relevant drug product specifications (CRDPS). It was recognized that understanding the impact of formulation and process variations on dissolution and in vivo performance is critical for most drug products formulated with poorly soluble drugs to ensure consistent product performance. The breakout sessions served as platforms for discussing controversial topics such as the clarification of dissolution terminology, PBPK model development and validation expectations, and approaches to set CRDPS. The meeting concluded with a commitment to continue the dialog between regulators, industry, and academia to advance overall product quality understanding.     

Impact of clinical pharmacist services delivered via telemedicine in the outpatient or ambulatory care setting: A systematic review

Background

Utilization of telemedicine allows pharmacists to extend the reach of clinical interventions, connecting them with patients and providers, but the overall impact of these services is under-studied.

Enhanced antibacterial nanocomposite mats by coaxial electrospinning of polycaprolactone fibers loaded with Zn-based nanoparticles

ZnO and Zn acetate nanoparticles were embedded in polycaprolactone coaxial-fibers and uniaxial-fibers matrices to develop potential antibacterial nanocomposite wound dressings (mats). Morphology, composition, wettability, crystallinity and fiber structure of mats were characterized. Antibacterial properties of mats were tested against E. coli and S. aureus by turbidity and MTT assays. The effect of UVA illumination (prior to bacteria inoculation) on mats’ antibacterial activity was also studied. Results showed that a coaxial-fibers design maintained nanoparticles distributed in the outer-shell of fibers and, in general, enhanced the antibacterial effect of the mats, in comparison to conventional uniaxial-fibers mats. Results indicated that mats simultaneously inhibited planktonic and biofilm bacterial growth by, probably, two main antibacterial mechanisms; 1) release of Zn²⁺ ions (mainly from Zn acetate nanoparticles) and 2) photocatalytic oxidative processes exerted by ZnO nanoparticles. Antibacterial properties of mats were significantly improved by coaxial-fibers design and exposure to UVA-light prior to bacteria inoculation.     

Contextualizing Relationship Education and Adolescent Attitude Toward Sexual Behavior: Considering Class Climate

Background

Using data from a statewide relationship education (RE) program targeting a diverse adolescent sample, this study examined RE implementation in classroom environments.

Objective

The purpose of this study was to explore (1) whether there is a beneficial RE program effect for change in individual attitudes toward sexual delay, (2) whether individual factors—student gender and sexual activity—predict change in attitudes toward sexual delay for students experiencing the intervention, and (3) whether classmate characteristics influence individual change in attitudes toward sexual delay.

Methods

This study utilized multilevel modeling procedures to examine both individual- and classroom-level predictors of change in attitudes toward sexual delay.

Results

At the individual level, results indicated that females demonstrated more change in attitudes toward sexual delay than males and students who were sexually active demonstrated less change toward sexual delay compared with students who were not sexually active. At the classroom level, both racial composition and the proportion of sexually active classmates influenced individual attitude change. Although students in classrooms with higher proportions of African American peers demonstrated less attitude change toward sexual delay, the proportion of sexually active peers in the classroom appeared to be a more salient aspect of classmate composition.

Conclusions

Overall, this study supports the importance of considering both individual characteristics as well as social context when assessing program experience and effectiveness. Implications for future research and practice are offered.

     

A multiple case study of data use practice in eight early childhood centres in the Republic of Trinidad and Tobago

ABSTRACT

Formative assessment and effective use of data to support student learning are key components of practice in early childhood (EC) centres. Although Trinidad and Tobago has developed an impressive EC care system, to decrease the achievement gap which international studies have shown to be significant in core subjects, educational planners must ensure that teachers make better use of data. This study explored data use practice in eight geographically diverse EC centres. Using maximum variation sampling, data were collected from focus group teacher interviews, observation and document analysis. Thematic analysis and constant comparison were used to identify differences across sites and to generate theory on practice. The theory identifies data use practice in an emerging Caribbean society lacking a robust data culture and with limited professional development opportunities. Implications for policy, professional sdevelopment and system reform of the EC sector in Trinidad and Tobago are included.     

Analysis of pedigree data in populations with multiple ancestries: Strategies for dealing with admixture in Caribbean Hispanic families from the ADSP

Multipoint linkage analysis is an important approach for localizing disease‐associated loci in pedigrees. Linkage analysis, however, is sensitive to misspecification of marker allele frequencies. Pedigrees from recently admixed populations are particularly susceptible to this problem because of the challenge of accurately accounting for population structure. Therefore, increasing emphasis on use of multiethnic samples in genetic studies requires reevaluation of best practices, given data currently available. Typical strategies have been to compute allele frequencies from the sample, or to use marker allele frequencies determined by admixture proportions averaged over the entire sample. However, admixture proportions vary among pedigrees and throughout the genome in a family‐specific manner. Here, we evaluate several approaches to model admixture in linkage analysis, providing different levels of detail about ancestral origin. To perform our evaluations, for specification of marker allele frequencies, we used data on 67 Caribbean Hispanic admixed families from the Alzheimer's Disease Sequencing Project. Our results show that choice of admixture model has an effect on the linkage analysis results. Variant‐specific admixture proportions, computed for individual families, provide the most detailed regional admixture estimates, and, as such, are the most appropriate allele frequencies for linkage analysis. This likely decreases the number of false‐positive results, and is straightforward to implement.     

Dietary Changes and Gut Dysbiosis in Children With Type 1 Diabetes

Objective: Gut dysbiosis in type 1 diabetes (T1D), characterized by high Bacteroides proportion, tends to reverse as T1D progresses, without reaching full recovery. Since diet influences microbiota structure, the aim was to evaluate the impact of dietary changes on Bacteroides proportion the first year of T1D evolution.

Methods: Dietary intake was assessed by 24-hour recalls and Bacteroides proportion by quantitative polymerase chain reaction, in 10 Mexican children (11.6 ± 1.92 years) with T1D at baseline and 3, 6 and 9 months' follow-up. Repeated measures analysis of variance and multiple linear regression were performed to compare ingested nutrients in relation with Bacteroides proportion. Effects over time were evaluated by mixed regression models.

Results: Patients with T1D decreased their energy (2621.89 to 1867.85 kcal, p = 0.028), protein (83.06 to 75.17 g, p = 0.012), and saturated fat consumption (40.83 to 25.23 g, p = 0.031) from baseline to 3 months, without posterior changes. Bacteroides proportion increased in the first months and tended to decrease at around 9 months (p > 0.05) and was positively correlated with saturated fat (β = 3.70, p = 0.009) and total carbohydrates (β = 0.73, p = 0.005) at 3 months. Carbohydrate consumption was related to decreased Bacteroides abundance over time (β = ?14.9, p = 0.004), after adjusting for glycosylated hemoglobin.

Conclusions: Besides autoimmunity, diet appears to have a central role determining the T1D-associated dysbiosis evolution.     

alpha- and epsilon-protein kinase C activity during smooth muscle cell apoptosis in response to gamma-radiation

The use of gamma-radiation in treatment of pelvic cancer is associated with injury of healthy surrounding tissues and disorders of intestinal motility; however, the cellular mechanisms involved are unclear. We tested the hypothesis that exposure of visceral smooth muscle cells (SMCs) to gamma-radiation induces apoptosis via activation of specific protein kinase C (PKC) isoforms. Cultured SMCs and slices from guinea pig ileum smooth muscle longitudinal layer (GPISMLL) were exposed to 10 to 50 Gy. Flow cytometry in gamma-radiated SMCs showed increased percentage of cells in the sub-G(0)/G(1) phase, a hallmark of apoptosis. gamma-Radiation-induced reduction in cell survival was partially but significantly alleviated with the PKC inhibitors. Sections of gamma-irradiated GPISMLL showed DNA fragmentation and apoptotic bodies analyzed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling method, whereas the plasma and nuclear membranes were preserved. Confocal microscopy in gamma-radiated SMCs labeled with annexin V-fluorescein showed an increase in apoptotic cells and phosphatidylserine externalization. Contraction of GPISMLL strips in response to KCl and acetylcholine was reduced in tissues exposed to 30 and 50 Gy. gamma-Radiation of GPISMLL caused an increase in PKC activity in the particulate fraction, a decrease in the cytosolic fraction, and increased particulate/cytosolic PKC activity ratio. Western blot analysis revealed significant amounts of alpha- and epsilon-PKC in the cytosolic fraction of control GPISMLL. gamma-Radiation caused an increase in the amount of alpha- and epsilon-PKC in the particulate fraction and a decrease in the cytosolic fraction. Data suggest that gamma-radiation induces apoptosis, growth arrest, and contractile dysfunction in visceral SMCs of GPISMLL via activation and translocation of alpha- and epsilon-PKC isoforms.