Cellular resistance to the antimelanoma immunotoxin ZME-gelonin and strategies to target resistant cells

 The development of cellular resistance to immunotoxins has been demonstrated in a variety of models and can involve a number of mechanisms. For the present study, an immunotoxin was utilized composed of an antimelanoma antibody ZME-018 recognizing a 240-kDa surface glycoprotein (gp 240) and the plant toxin gelonin. Human melanoma cells (A375-M) were grown in the presence of increasing amounts of ZME-gelonin and a clonal variant (A-375-ZR) was developed that was 100-fold resistant to ZME-gelonin compared to parental cells. Scatchard analysis showed that the A375-M parental cells had 260×10³ ZME-gelonin-binding sites/cell with relatively low affinity (5 nM). In contrast, resistant A375-ZR cells demonstrated a reduced number of low-affinity sites (160×10³/cell), but showed a small number (47×10³) of higher-affinity sites (0.8 nM). Internalization rates and degradation rates of ¹²⁵I-labeled ZME-gelonin were identical in both the parental and resistant cells. A375-ZR cells were found to be more resistant to vincristine and doxorubicin than were parental cells. Both cell lines were almost equally sensitive to native gelonin, 5-fluorouracil (5-FU), cisplatin, melphalan, carmustine, interferon γ (IFNγ) and IFNα. In addition, both cell lines were equally sensitive to another gelonin-antibody conjugate that binds to cell-surface, GD₂ (antibody 14G₂A). However, resistant cells were twice as sensitive to the cytotoxic effects of etoposide than were parental cells. Finally, a variety of agents were tested in combination with ZME-gelonin against A375-ZR cells in an attempt to identify agents to augment immunotoxin cytotoxic effects against resistant cells. The agents 5-FU, cisplatin, IFNγ, IFNα, and etoposide were the most effective in augmenting the cytotoxicity of ZME-gelonin against resistant cells. These studies suggest that development of resistance to one immunotoxin does not cause development of cross-resistance to other gelonin immunotoxins. Further, specific biological response modifiers and chemotherapeutic agents may be effective in augmenting the effectiveness of immunotoxins and specifically targeting or reducing the emergence of immunotoxin-resistant cells. Received: 15 March 1995 / Accepted: 28 November 1995     

Sexual behavior during successive ejaculations in bonnet and pigtail macaques

During tests of sexual behavior which permitted multiple ejaculations, male bonnet and pigtail macaques were found to differ on a number of traditionally defined behavioral parameters. Although pigtail tests were terminated by a more stringent criterion, they were longer in duration and more ejaculations were recorded than in the bonnet tests. Pigtail males required relatively more intromissions for initial ejaculations and somewhat fewer on successive ejaculations. Bonnets, on the other hand, generally ejaculated on the first mount of a test and then exhibited increased numbers of intromissions to successive ejaculations. Although both species exhibited increases in successive postejaculatory intervals, the changes were more gradual for the pigtails.     

Location-restricted dyadic interactions and maternal patterns

The purpose of this study was to determine the impact of infant restraint on dyadic interactions and maternal foraging patterns. Five bonnet macaque (Macaca radiata) mother-infant dyads were observed under three conditions: high foraging demand for the mothers with nonrestrained contact between mothers and infants (HFD-NRC), high foraging demand with restrained contact (HFD-RC), and low foraging demand with restrained contact (LFD-RC). In the restrained contact conditions the infants lived in a nursery within the group pen that allowed dyadic nursing, contact, proximity, and grooming, but prevented the infants from being with their mothers in the remaining portions of the pen, including the foraging area. Observations began when the infants were a mean of 5.4 months old. HFD-RC resulted in decreased dyadic contact relative to HFD-NRC, but did not significantly affect foraging task engagement; there were, however, marked individual differences in the response patterns of the mothers. Dyadic contact was also decreased during the LFD-RC condition, but maternal patterns under low demand resulted in lower levels of infant contact initiation. This study demonstrated the feasibility of a nursery-restrained rearing paradigm in exploring the strategic patterns of coping with conflicting environmental and maternal demands in bonnet macaque mothers. © 1993 Wiley-Liss, Inc.     

Sensory Modulation and Sleep Quality among Adults with Learning Disabilities: A Quasi-Experimental Case-Control Design Study

PurposeFollowing the International Classification of Functioning, Disability and Health (ICF) concepts, this study examines body functions such as sensory modulation and sleep quality among adults with learning disabilities (LD).MethodsOne hundred and ten participants, 55 adults with LD and 55 matched controls (mean age 30 years) filled in a socio-demographic questionnaire, the Adults/Adolescents Sensory Profile (AASP), and the Mini Sleep Questionnaire (MSQ). Chi-tests, Mann-Whitney tests, and Kolmogorov-Smirnov tests were conducted to examine group differences related to socio-demographic characteristics and body functions. Correlation and regression analyses were conducted to examine relationships between body functions.ResultsSignificant differences were found between the groups in: (a) unique socio-demographic variables: high-schools attended, family status and number of children; (b) body functions: low registration and sensory sensitivity (p < .001), sensory avoiding (p = .002), sensory seeking (p = .021) and sleep quality (p < .001). Significant correlations were found between AASP subscale scores and the MSQ final score in each group. Regression analysis revealed that for the entire sample (N = 108), low registration accounted for 10.2% of the variance of sleep quality above group membership (p < .001), while in a separate examination of adults with LD (n = 53), low registration accounted for 19.9% of the variance of sleep quality (p < .001).ConclusionsAdults with LD need to be studied through a health-related perspective such as the ICF model to gain further understanding of their unique characteristics and daily needs. Sensory and sleep functions of adults with LD should be further studied in the context of health related quality of life.     

Variants in the interleukin-1 alpha and beta genes,and the risk for periodontal disease in dogs

Elevated levels of interleukin-1 (IL-1) have been shown to amplify the inflammatory response against periodontopathogenic bacteria. In humans, polymorphisms in the IL1A and IL1B genes are the most well-studied genetic polymorphisms associated with periodontal disease (PD). In contrast to human, there is a lack of knowledge on the genetic basis of canine PD. A case–control study was conducted in which a molecular analysis of dog IL1A and IL1B genes was performed. Of the eight genetic variants identified, seven in IL1A gene and one in IL1B gene, IL1A/1_g.388A >C and IL1A/1_g.521T >A showed statistically significant differences between groups (adjusted OR (95% CI): 0.15 (0.03–0.76), P= 0.022; 5.76 (1.03–32.1), P= 0.046, respectively). It suggests that in the studied population the IL1A/1_g.388C allele is associated with a decreased PD risk, whereas the IL1A/1_g.521A allele can confer an increased risk. Additionally, the IL1A/2_g.515G >T variation resulted in a change of amino acid, i.e. glycine to valine. In silico analysis suggests that this change can alter protein structure and function, predicting it to be deleterious or damaging. This work suggests that IL1 genetic variants may be important in PD susceptibility in canines.