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Biomedical subjects

N A Brooks

Publications and source records attributed to N A Brooks.

11 recordsLinked to original sources
PubMed2001

Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity.

A novel sequence-selective pyrrolobenzodiazepine (PBD) dimer 5 (SJG-136) has been developed that comprises two C2-exo-methylene-substituted DC-81 (3) subunits tethered through their C8 positions via an inert propanedioxy linker. This symmetric molecule is a highly efficient minor groove interstrand DNA cross-linking agent (XL(50) = 0.045 microM) that is 440-fold more potent than melphalan. Thermal denaturation studies show that, after 18 h incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, it increases the T(m) value by 33.6 degrees C, the highest value so far recorded in this assay. The analogous dimer 4 (DSB-120) that lacks substitution/unsaturation at the C2 position elevates melting by only 15.1 degrees C under the same conditions, illustrating the effect of introducing C2-exo-unsaturation which serves to flatten the C-rings and achieve a superior isohelical fit within the DNA minor groove. This behavior is supported by molecular modeling studies which indicate that (i) the PBD units are covalently bonded to guanines on opposite strands to form a cross-link, (ii) 5 has a greater binding energy compared to 4, and (iii) 4 and 5 have equivalent binding sites that span six base pairs. Dimer 5 is significantly more cytotoxic than 4 in a number of human ovarian cancer cell lines (e.g., IC(50) values of 0.0225 nM vs 7.2 nM, respectively, in A2780 cells). Furthermore, it retains full potency in the cisplatin-resistant cell line A2780cisR (0.024 nM), whereas 4 loses activity (0.21 microM) with a resistance factor of 29.2. This may be due to a lower level of inactivation of 5 by intracellular thiol-containing molecules. A dilactam analogue (21) of 5 that lacks the electrophilic N10-C11/N10'-C11' imine moieties has also been synthesized and evaluated. Although unable to interact covalently with DNA, 21 still stabilizes the helix (Delta T(m) = 0.78 degrees C) and has significant cytotoxicity in some cell lines (i.e., IC(50) = 0.57 microM in CH1 cells), presumably exerting its effect through noncovalent interaction with DNA.

Antineoplastic Agents↗
PubMed1998

Experimental rationale for treatment of high-risk human melanoma with zinc chloride fixative paste. Increased resistance to tumor challenge in murine melanoma model.

BACKGROUND: Fixed-tissue micrographic surgery (Mohs) of melanoma has been shown by retrospective analysis to improve 5-year survival. OBJECTIVES: To determine whether zinc chloride fixative paste acts as an immune adjuvant to increase host resistance to melanoma. METHODS: We performed a murine study using the poorly immunogenic B16 melanoma of C57Bl6J mice, and the more immunogenic K1735p melanoma of C3H/HeN mice. Tumors were treated with zinc chloride paste and excised 24 hours later (Group 1), or simply excised (Group 2). Mice were challenged 7 days later with injection of melanoma cells at a distant site, and tumor growth in this second site was followed. RESULTS: K1735p melanomas developed at the challenge site in 69% of mice treated with excision versus 32% of mice treated with zinc chloride fixation (P < 0.025). Development of B16 melanoma was not altered by zinc chloride fixation. CONCLUSION: Zinc chloride fixation of the more immunogenic K1735p melanoma increased resistance to subsequent tumor challenge, suggesting that zinc chloride fixative paste acts as an immune adjuvant.

Animals↗
PubMed1992

Fixed-tissue micrographic surgery in the treatment of cutaneous melanoma. An overlooked cancer treatment strategy.

Many physicians have overlooked the value of adding zinc chloride tissue fixation prior to Mohs micrographic surgery, partly because of the absence of randomized clinical comparison trials. Nevertheless, historic control data indicate a survival benefit in the treatment of cutaneous melanoma. Three possible mechanisms are: 1) prevention of release of viable cells into circulation during surgery, 2) avoidance of disruption of clinically invisible satellite deposits, and 3) stimulation of a local inflammatory reaction and possible immune response.

Chlorides↗
PubMed1991

Users' responses to assistive devices for physical disability.

A mailed survey of scientists and engineers with disabilities was conducted to investigate how assistive devices for disability utilized in various social settings were perceived by persons with disabilities who also maintained valuable occupational positions. The respondents (N = 595) reported assistive-device utilization in social settings and user attitudes toward using assistive mechanical aids. The minority-group conceptual framework guided analysis of assistive technology as a symbol of disability. Variations in device use within public and private settings and differences in attitudes according to demographic and disability characteristics also are described. Findings show general user satisfaction with devices. Utilization varies among social settings and also varies by disability type, especially between persons with sensory impairment and those with nonsensory impairment. Public responses were not perceived to be problematic, although users do indicate that the actual application of devices may be unsatisfactory. Users' suggestions for further research chiefly propose examination of the systems that develop and distribute assistive devices. Results encourage examination of socioeconomic arrangements that reinforce the minority position of people with disabilities by restricting access to aids perceived as beneficial to social roles.

Attitude to Health↗
PubMed1984

Opportunities for health promotion: including the chronically ill and disabled.

One of the aims of health promotion and illness prevention is to reduce the prevalence of chronic disease that is so apparent in the developed countries, yet the very individuals who already have chronic diseases and disabling conditions constitute a sizeable population which could contribute to health promotion programs. There are two chief elements which argue for an extension of health promotion toward the chronically ill and disabled: (1) the lifestyle management which is characteristic of health promotion is similar in many respects to the comprehensive self-care regimens followed by chronically ill persons, and (2) the philosophy of independent living for disabled persons shares social foundations with the concept of health promotion and could add the strength of social advocacy to health promotion. This paper examines social and medical variables linking the two health trends of health promotion and independent living for disabled persons. Observations of a U.S. independent living program, The Timbers, are reported to illustrate an active combination of the two philosophies. Finally, sociological implications are presented, with a focus on the potential of health promotion programs.

Chronic Disease↗
PubMed1984

Curettage and shave excision. A tissue-saving technic for primary cutaneous carcinoma worthy of inclusion in graduate training programs.

Curettage and electrodesiccation, the customary treatment for primary basal and squamous cell carcinomas, lacks histologic control and standardization. A review of the literature cites these factors as potential causes for undesirable recurrence rates, especially in cosmetically sensitive areas. Curettage and shave excision offers histologic control, yet with no more sacrifice of normal tissue than curettage and electrodesiccation. An experimental study with 100 patients is described in which curettage and shave excision was used, instead of curettage and electrodesiccation, to treat primary carcinomas 1.0 cm or less. It is suggested that curettage and shave excision, while simple in concept, requires formal training and warrants consideration for inclusion into graduate training programs as an alternative effective treatment for primary carcinomas.

Adult↗
PubMed1982

Social-psychological adjustment to multiple sclerosis. A longitudinal study.

This study employs a longitudinal design to analyze the adjustment process of 103 people diagnosed with multiple sclerosis and in the middle and later stages of their illness careers. The mean age of the sample at Time 2 is 52 years, and mean duration since diagnosis is 17 years. A highly reliable self concept measure is the indicator of adjustment and changes in adjustment from T1 (1974) to T2 (1981). Four sets of variables are analyzed in their relationship to adjustment: (1) socio-demographic; (2) disease-related; (3) medical; and (4) social-psychological. Females are more likely than males to show positive adjustment (improving self concepts). Hours of employment and living arrangement are also related to the adjustment process. The vast majority of respondents show only slight decline in mobility, but among the disease related variables, number of episodes (exacerbations) in past seven years is the strongest predictor of changes in adjustment. Nearly half the respondents seek medical attention for their M.S. once a year or less, and the choice of health care professional is related to changes in the course of the disease. Subjects with an internal locus of control have more positive adjustment scores. Those who say they cope through acceptance of the disease show improvements in self concept while those reporting religion or family as major coping strategies have decreasing self concepts. Results indicate that the majority make satisfactory adjustment as indicated by maintenance of positive self concepts over the 7 year period, although the disease is chronic and progressive. For patients in the middle and later stages of illness careers, the data suggest comprehensive rehabilitation efforts that enhance autonomy and develop the social-psychological resources of the lifestyle.

Adaptation, Psychological↗