Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer

Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with ²¹²Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of ²¹²Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of ²¹²Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of ²¹²Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of ²¹²Pb-NG001.     

Characterization of rubber-cellulose-fibre composites by mechanical measurements and electron microscopy

Mechanical measurements, SEM micrographs and crosslink density measurements on cellulose-fibre-filled natural rubber suggest that there are bonds between untreated cellulose fibres and the rubber matrix. Mechanical tests indicate that the dispersion or lack of dispersion of the fibres in the matrix is at least as influential a parameter in determining the strength of the composite as is the adhesion between fibre and matrix. Stress/strain measurements indicate that there is no obvious correlation between adhesion and the shape of the stress/strain curve unless the curve is clearly jagged.     

Effects of sibling relationships on preschoolers' behavior at home and at school.

Observed the social behavior of 34 36–64 mo olds (17 males and 17 females) both in their homes and in their preschools to determine the patterning of interactions among siblings and the consistency in children's interactions with siblings and peers. Results show that at home, preschoolers with older siblings received more aggressive and prosocial behavior than did preschoolers without older siblings; they also played frequently with their older siblings. Preschoolers with younger siblings were more dominant in their interactions than were preschoolers without younger siblings, but they displayed certain types of verbal behavior less often, probably because their young siblings had limited language skills. Indicators of sibling status were not strongly related to behavior at school, but girls who did not have any brothers spent more time unoccupied or as onlookers. Few of the correlations between home and school behaviors were significant, but Ss who were more aggressive toward siblings and Ss who were more often onlookers or unoccupied at home showed similar behavior with peers. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Automated classification of phonological errors in aphasic language

Using heuristically guided state space search, a prototype program has been developed to simulate and classify phonemic errors occurring in the speech of neurologically impaired patients. Simulations are based on an interchangeable rule/operator set of elementary errors which represent a theory of phonemic processing faults. This work is significant because it introduces and evaluates a novel approach to error simulation and classification, provides a prototype simulation tool for neurolinguistic research, and forms the initial phase of a larger research effort involving computer modelling of neurolinguistic processes.     

Assessing the elements contributing to a "mapping" deficit: a targeted treatment study

Aphasic patients with excellent comprehension of word meanings frequently fail to understand simple declarative sentences in which either of two nouns could reasonably serve as agent of a transitive action. This study employed targeted treatment of this comprehension problem in a chronic aphasic patient (E.A.) in an attempt to isolate the source or sources of his comprehension failure. Treatment exercises that relied on error feedback in sentence-picture matching or verification initially were not effective. Comprehension of active and passive sentences improved only after both structures were explicitly compared and linked to a picture. Subsequently E.A. maintained consistently accurate interpretation of both sentence types in the treatment exercises as long as the full sentence was available to him. E.A. learned to assign thematic roles using a limited set of cues in the surface structure. Although improvement was reported in untreated sentences, the degree of generalization and the level of performance differed across tasks and appeared to be attributable to cognitive impairments that were not addressed by the treatment. Results are interpreted as evidence suggesting that multiple impairments contribute to failure of sentence comprehension tasks.     

Failure processes within ceramic coatings at high temperatures

Plasma sprayed coatings have a complex structure which is produced by the overlaying of many molten or semi-molten particles in the diameter range of 20 to 120 μm. There is a need to characterize the failure behaviour of coatings and this has been carried out by using acoustic emission (AE) methodology. Coatings of NiCrAIY bond coat with a zirconia-12 wt% yttria overlay were applied to discshaped specimens of U-700 alloy. A waveguide of 1 mm diameter platinum was TIG welded to the specimen and allowed it to be suspended in a tubular furnace. The specimen was thermally cycled to 1150° C and the AE monitored. One method of examining the AE is from the viewpoint of the accumulative count data. It is also convenient to establish the temperatures for “initial” AE and “significant” AE (i.e., the temperature at which 100 counts is exceeded) so that coatings may be compared. Several other analyses have been carried out with the aim of establishing parameters which are related to the crack size and crack population. These studies have been used to postulate types of cracking mechanisms which may occur in plasma sprayed coatings during thermal cycling. It is shown that microcracking gave rise to a large amount of AE. However, this coating still survived more thermal cycles than a coating which exhibited macrocracking events. Data of this nature will be presented and the results discussed.     

Multiple regulatory events influence human cytomegalovirus DNA polymerase (UL54) expression during viral infection

The human cytomegalovirus (HCMV) DNA polymerase gene (UL54; also called pol) is a prototypical early gene in that expression is mandatory for viral DNA replication. Recently, we have identified the major regulatory element in the UL54 promoter responsive to the major immediate early (MIE) proteins (UL122 and UL123) (J.A. Kerry, M.A. Priddy, and R. M. Stenberg, J. Virol. 68:4167-4176, 1994). Mutation of this element, inverted repeat sequence 1 (IR1), abrogates binding of cellular proteins to the UL54 promoter and reduces promoter activity in response to viral proteins in transient-transfection assays. To extend our studies on the UL54 promoter, we aimed to examine the role of IR1 in UL54 regulation throughout the course of infection. These studies show that viral proteins in addition to the MIE proteins can activate the UL54 promoter. Proteins from UL112-113 and IRS1/TRS1, recently identified as essential loci for transient complementation of HCMV oriLyt-dependent DNA replication, were found to function as transactivators of the UL54 promoter in association with MIE proteins. UL112-113 enhanced UL54 promoter activation by MIE proteins three- to fourfold. Constitutive expression of UL112-113 demonstrated that the MIE protein dependence of UL112-113 transactivational activity was not related to activation of cognate promoter sequences, suggesting that UL112-113 proteins function in cooperation with the MIE proteins. Mutation of IR1 was found to abrogate stimulation of the UL54 promoter by UL112-113, suggesting that this element is also involved in UL112-113 stimulatory activity. These results demonstrate that additional viral proteins influence UL54 promoter expression in transient-transfection assays via the IR1 element. To confirm the biological relevance of IR1 in regulating UL54 promoter activity during viral infection, a recombinant virus construct containing the UL54 promoter with a mutated IR1 element regulating expression of the chloramphenicol acetyltransferase (CAT) reporter gene (RVIRmCAT) was generated. Analysis of RVIRmCAT revealed that mutation of IR1 dramatically reduces UL54 promoter activity at early times after infection. However, at late times after infection CAT expression by RVIRmCAT, as assessed by RNA and protein levels, was approximately equivalent to expression by wild-type RVpolCAT. These data demonstrate IR1-independent regulation of the UL54 promoter at late times after infection. Together these results show that multiple regulatory events affect UL54 promoter expression during the course of infection.     

Aphasic patients' sensitivity to structural and meaning violations when monitoring for nouns and verbs in sentences.

Aphasic patients with and without impairment of semantically reversible sentence comprehension and 2 groups of normal controls were monitored for unambiguous noun or verb targets while listening to sentence pairs. Four conditions of target-word/sentence-pair congruence were created by manipulating the predictability of the target word from a context sentence and by inserting targets into structures that were appropriate or inappropriate for the target's grammatical class. Normal and aphasic listeners showed comparable sensitivity to structural violations under different conditions of semantic predictability, and there was little difference in the performance of aphasic patients with and without comprehension disorder. These results support the argument that normal sensitivity to syntactic requirements can be found in patients with reversible sentence comprehension disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)