Pectic Galactan Polysaccharide-Based Gene Delivery System for Targeting Neuroinflammation

Treating neuroinflammation-related injuries and disorders through manipulation of neuroinflammation functions is being heralded as a new therapeutic strategy. In this study, a novel pectic galactan (PG) polysaccharide based gene therapy approach is developed for targeting reactive gliosis in neuroinflammation. Galectin-3 (Gal-3) is a cell protein with a high affinity to β-galactoside sugars and is highly expressed in reactive gliosis. Since PG carries galactans, it can target reactive gliosis via specific carbohydrate interaction between galactan and Gal-3 on the cell membrane, and therefore can be utilized as a carrier for delivering genes to these cells. The carrier is synthesized by modifying quaternary ammonium groups on the PG. The resulting quaternized PG (QPG) is found to form complexes with plasmid DNA with a mean diameter of 100 nm and have the characteristics required for targeted gene therapy. The complexes efficiently condense large amounts of plasmid per particle and successfully bind to Gal-3. The in vivo study shows that the complexes are biocompatible and safe for administration and can selectively transfect reactive glial cells of an induced cortical lesion. The results confirm that this PG-based delivery system is a promising platform for targeting Gal-3 overexpressing neuroinflammation cells for treating neuroinflammation-related injuries and neurodegenerative diseases.     

Quantifying the limits of CAR T-cell delivery in mice and men

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10–100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.     

An extended pharmacokinetic/pharmacodynamic model describing quantitatively the influence of plasma protein binding, tissue binding, and receptor binding on the potency and time course of action of drugs

An extended pharmacokinetic/pharmacodynamic (PK/PD) model is presented, in which the effect of binding of the drug to plasma proteins and to tissue binding sites in a peripheral compartment, and nonspecific and receptor binding in the effect compartment are taken into account. It represents an extension of the classical Sheiner model, and the model proposed by Donati and Meistelman. The present model is characterized by the following parameters: Kue (exit rate constant of unbound drug from the effect compartment), Pue (ratio of the unbound clearances to and from the effect compartment), fue (fraction of drug in effect compartment that is not bound to nonspecific binding sites), Kd (equilibrium dissociation constant of drug-receptor binding), and Rtot (concentration of receptor binding sites in effect compartment). The rate of association and dissociation of the drug-receptor complex can be incorporated in the model. The influence of the pharmacokinetic parameters (V1, V2, fu, fu2, CLu10, CLu20, CLu12, CLu21) and the PK/PD model parameters (kue, Pue, fue, Kd, Rtot) on various dynamic parameters is analyzed. These include potency (single dose needed to produce 90% effect, ED90), constant infusion dosing rate needed to maintain a constant effect of 90%, time to maximum effect (onset time), and duration to 90% recovery. The neuromuscular blocking agent vecuronium is used as an example. It is shown that both potency and time course of action are strongly dependent on the ratio V1/fu, CLu10, kue, Pue (at equipotent doses the time course is not affected by Pue), fue, Kd, and Rtot (only if Rtot is high), whereas they are less affected by the ratio V2/fu2, CLu20, CLu12, and CLu21. In general, the model parameters affect the ED90 and the time course of action in the same direction, e.g., an increase of V1 results in an increase of ED90 and an increase of onset time and duration. However, the unbound clearance CLu10, the intercompartmental unbound clearance CLu12 and the receptor affinity Kd have an opposite effect on ED90 and the time course parameters, e.g., an increase of CLu10 results in an increase of ED90 and a decrease of onset time and duration. This effect may be responsible for the inverse relationship between onset time and potency of neuromuscular blocking drugs observed in animal experiments and clinical studies. We demonstrate that PK/PD analysis using the traditional effect compartment model (Sheiner model) results in an apparent value of keo, which is a function of kue, fue, Kd, Rtot, as well as the unbound drug concentration in the effect compartment Cue. On the other hand, the model proposed by Donati and Meistelman gives correct values of keo (equal to the product fue.kue), but the receptor affinity Kd and the receptor density Rtot obtained by this method are apparent values, which depend on fu, fue, and Pue.     

Non-Hodgkin lymphoma of the central skull base: MR manifestations

OBJECTIVE: The aim of this study was to demonstrate the MR characteristics of non-Hodgkin lymphoma of the skull base to help in the differential diagnosis of this neoplasm from other conditions. MATERIALS AND METHODS: MR of five patients, 7-64 years old, with pathologically proved lymphomas of the skull base were reviewed. Three cases had primary skull base lesions involving the sphenoid bone and the cavernous sinus. One case with a nasal cavity lesion involving the skull base and one with a relapsing skull base lesion of previously treated tonsillar lymphoma were included. RESULTS: The lesions had signal intensities that were similar to that of gray matter of brain on both T1- and T2-weighted imaging. Bilateral cavernous sinuses were involved with encasement of internal carotid arteries in every case. Postcontrast MR showed homogeneous enhancement of the tumor with dural infiltration along the planum sphenoidale, clivus, or tentorium. The clivus was destroyed or replaced by tumors in adult cases but in two children the clivus was preserved with intact sphenooccipital synchondrosis. In one case the tumor extended to the extracranial portion through the jugular foramen. CONCLUSION: The MR findings of a permeative lesion of the skull base, invasion of the cavernous sinus without arterial narrowing, infiltration along the dural surface, and an iso- or hypointensity with brain on T2-weighted imaging should suggest lymphoma.     

Live animal performance, carcass traits, and meat palatability of calf- and yearling-fed cloned steers

Two groups of Brangus steers produced by nuclear transplantation cloning were used in parallel studies investigating the impact of calf- and yearling-feeding. The first group (n = 8) were fed as calves (CF; n = 4) or yearlings (YF; n = 4) to a constant age end point of 16 mo. The second group (n = 10) were fed as calves (CF; n = 5) or yearlings (YF; n = 5) to a constant live weight end point (530 kg). When slaughtered at the same age, CF and YF steers did not differ (P > .05) in feedlot ADG, but the CF steers were heavier and had higher dressing percentages, numeric yield grades, and quality grades (P < .05). Top loin steaks from the groups of steers did not differ (P > .05) in palatability traits. When fed to a constant live weight, the YF steers gained more rapidly (P < .05) and had lower (P < .05) numeric yield grades than did CF steers. Again CF steers had higher (P < .05) dressing percentages. There was no difference (P > .05) between the treatments in carcass quality grade or meat palatability characteristics. Thus, when finished to a constant weight end point, YF steers gained more rapidly, with no adverse effects on carcass quality grade or palatability traits; however, CF steers consistently produced higher dressing percentages, largely due to greater external fatness.     

Analysis of volatiles evolved during high-temperature treatment of thermally stable polymers. I. Nitrogen-containing acetylene-terminated resin

Cured samples of a nitrogen-containing acetylene-terminated resin, N,N′-(1,3-phenylene-dimethylidene)bis(3-ethynylaniline), have been heated at 10°C/min up to 900°C in a pyroprobe attached to a gas chromatograph/mass spectrometer (GC/MS). Analysis of the volatiles evolved during heating identified both gases and higher boiling compounds. The major higher boiling compounds are benzene, toluene, xylene, aniline, benzonitrile, m-methylaniline, and m-methylbenzonitrile; the gases include ammonia, methane, and traces of carbon dioxide. Correlations between sample temperature and the evolution of each of these compounds have been made. The onset of all volatile formation occurs between 450 and 500°C. The higher boiling volatiles peak, then end by approximately 700°C, while the gases peak then fall off but are still being evolved at 900°C. Average weight loss measurements of 13.6% at 700°C and 15.7% at 900°C agree with previously published thermogravimetric analysis (TGA) data. © 1993 John Wiley & Sons, Inc.     

Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin

Glycoprotein 330 (gp330) is a member of a family of endocytic receptors related to the low density lipoprotein receptor. gp330 has previously been shown to bind a number of ligands in common with its family member, the low density lipoprotein receptor-related protein (LRP). To identify ligands specific for gp330 and relevant to its localization on epithelia such as in the mammary gland, gp330-Sepharose affinity chromatography was performed. As a result, a 70-kDa protein was selected from human milk and identified by protein sequencing to be apolipoprotein J/clusterin (apoJ). Solid-phase binding assays confirmed that gp330 bound to apoJ with high affinity (Kd = 14.2 nM). Similarly, gp330 bound to apoJ transferred to nitrocellulose after SDS-polyacrylamide gel electrophoresis. LRP, however, showed no binding to apoJ in either type of assay. The binding of gp330 to apoJ could be competitively inhibited with excess apoJ as well as with the gp330 ligands apolipoprotein E, lipoprotein lipase, and the receptor-associated protein, a 39-kDa protein that acts to antagonize binding of all known ligands for gp330 and LRP. Several cultured cell lines that express gp330 and ones that do not express the receptor were examined for their ability to bind and internalize 125I-apoJ. Only cells that expressed gp330 endocytosed and degraded radiolabeled apoJ. Furthermore, F9 cells treated with retinoic acid and dibutyryl cyclic AMP to increase expression levels of gp330 displayed an increased capacity to internalize and degrade apoJ. Cellular internalization and degradation of radiolabeled apoJ could be inhibited with unlabeled apoJ, receptor-associated protein, and gp330 antibodies. The results indicate that gp330 but not LRP can bind to apoJ in vitro and that gp330 expressed by cells can mediate apoJ endocytosis leading to lysosomal degradation.     

Should industrial/organizational psychologists be licensed?

A historical review of licensing among industrial/organizational (I/O) psychologists demonstrates that the American Psychological Association (APA) policy on such licensing is inconsistent. Arguments for and against licensure for this group are presented. Job analysis and APA data are drawn upon to show that few I/O activities may pose the personal risk that would seem to require the protection of a license. Alternatives are discussed for changes in present APA policy and state licensing requirements. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)