Biomedical subjects

Deborah Lewis

Publications and source records attributed to Deborah Lewis.

9 recordsLinked to original sources

PubMed2006

Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction.

The biarylpyrazole, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 1) has been shown to act as an inverse agonist/antagonist at the cannabinoid CB1 receptor. Our previous mutant cycle study suggested that K3.28(192) is involved in a direct interaction with the C-3 substituent of 1 in wild-type (WT) CB1.(1) However, these results did not establish what part of the C-3 substituent of 1 is involved in the K3.28(192) hydrogen bond, the carboxamide oxygen or the piperidine nitrogen. Furthermore, our previous calcium channel assay results for 5-(4- chlorophenyl)-3-[(E)-2-cyclohexylethenyl]-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole (VCHSR; 2) (an analogue of 1 that lacks hydrogen-bonding capability in its C-3 substituent) showed that this compound acts as a neutral antagonist, a result that is in contrast to 1, which acts as an inverse agonist in this same assay.(1) These results suggested a relationship between biarylpyrazole interaction with K3.28(192) at CB1 and inverse agonism, but these results were for a single pair of compounds (1 and 2). The work presented here was designed to test two hypotheses derived from our modeling and mutant cycle results. The hypotheses are as follows: (1) it is the carboxamide oxygen of the C-3 substituent of 1 that interacts directly with K3.28(192) and (2) the interaction with K3.28(192) is crucial for the production of inverse agonism for biarylpyrazoles such as 1. To determine whether the carboxamide oxygen or the piperidine nitrogen of the C-3 substituent may be the interaction site for K3.28(192), we designed, synthesized, and evaluated a new set of analogues of 1 (3-6, Chart 1) in which modifications only to the C-3 substituent of 1 have been made. In each case, the modifications that were made preserved the geometry of this substituent in 1. The absence of the piperidine nitrogen was not found to affect affinity, whereas the absence of the carboxamide oxygen resulted in a reduction in affinity. CB1 docking studies in an inactive state model of CB1 resulted in the trend, 3,1<5,4<2<6 for ligand/CB1 interaction energies. This trend was consistent with the trend in WT CB1 Ki values versus [3H]CP55,940 reported here. In calcium channel assays, all analogues with carboxamide oxygens (1, 3, and 4) were found to be inverse agonists, whereas those that lacked this group (2, 5, and 6) were found to be neutral antagonists. Taken together, these results support the hypothesis that it is the carboxamide oxygen of the C-3 substituent of 1 that engages in a hydrogen bond with K3.28(192) in WT CB1. Furthermore, functional results for 1-6 support the hypothesis that the interaction of 1 with K3.28(192) may be key to its inverse agonism.

Amides↗

PubMed2006

Phase II study of neoadjuvant docetaxel/ vinorelbine followed by surgery and adjuvant doxorubicin/cyclophosphamide in women with stage II/III breast cancer.

BACKGROUND: The purpose of this study was to evaluate the combination of docetaxel plus vinorelbine as neoadjuvant chemotherapy for stage II/III locally advanced breast cancer. PATIENTS AND METHODS: Eligible women with stage IIA-IIIB or locoregional stage IV breast cancer were treated before surgery with 6 cycles of docetaxel 60 mg/m2 and vinorelbine 45 mg/m2, repeated every 2 weeks with granulocyte colony-stimulating factor and quinolone prophylaxis. Pathologic complete response (pCR), viewed as an early surrogate for disease-free and overall survival, was the primary efficacy endpoint. Sixty patients were enrolled; 60% had T3 or T4 lesions, 67% had clinically palpable lymph nodes, and 52% were hormone receptor positive. RESULTS: Fifty-nine patients were evaluable for pathologic response; 16 (27%) exhibited pCR in the breast alone (T0 Tis NX), 20% exhibited a pCR in the breast and lymph nodes (T0 Tis N0), 24 (41%) had < 5 mm of residual tumor, and 28 (47%) had node-negative disease at surgery. Relative dose intensity was 96% for docetaxel and 95% for vinorelbine. The clinical response rate was 98% (59 of 60 patients), including 38 complete responses (63%). Grade 3/4 neutropenia (95%), neutropenic fever (22%), mucositis (5%), and pulmonary toxicity (5%) occurred in >or= 5% of patients. Constipation was seen early but became insignificant after incorporating a prophylactic laxative regimen. Other toxicities have been minimal. CONCLUSION: With a clinical response rate of 98% and an in-breast pCR rate of 27%, docetaxel/vinorelbine is among the most active neoadjuvant regimens reported for locally advanced breast cancer. Docetaxel/vinorelbine can be administered in a dose-dense fashion while maintaining relative dose intensity. However, there was a significant incidence of fever and neutropenia despite the use of prophylactic growth factors and quinolones, indicating that lower doses of docetaxel/vinorelbine should be evaluated in future studies.

Adult↗

PubMed2005

Caring Connection: developing an Internet resource for family caregivers of children with cancer.

This poster will describe the development of a family-focused, web-based resource, the "Caring Connection", designed to provide individualized clinical information, patient-centered information resources, and access to online family-provider and family-to-family communication for caregivers of children with cancer. Data from structured interviews with family caregivers and healthcare providers describe their current Internet use and information needs. Website prototype development and user testing provide additional insights that are informing the ongoing design of the "Caring Connection" website.

Caregivers↗

PubMed2004

Prophylactic bilateral nephrectomies in two paediatric patients with missense mutations in the WT1 gene.

BACKGROUND: Denys-Drash syndrome (DDS) is associated with mutations of the Wilms' tumour 1 (WT1) gene, and is characterized by pseudohermaphroditism, a progressive glomerulopathy, and the development of Wilms' tumour. More than 90% of patients with DDS who carry constitutional intragenic WT1 mutations are at high risk (90%) for the development of Wilms' tumour. WT1 is a signalling protein with 90% of WT1 mutations occurring in the WT1 zinc finger region as single nucleotide polymorphisms, the majority of which are missense mutations. METHODS: Constitutional DNA was extracted from peripheral blood. Direct sequencing and restriction enzymes were employed to analyse mutations. RESULTS: Two children, 46XY males who had evidence of pseudohermaphroditism, hypogonadism and renal failure with a glomerulopathy atypical for DDS, but no Wilms' tumour or nephroblastomatosis, on investigation, prior to transplant, were identified with missense mutations in the WT1 gene, in exons 8 and 9, respectively. The decision to do prophylactic nephrectomies was based on the genetic identification of WT1 mutations supporting a diagnosis of incomplete DDS, with the potential for increased risk of malignancy with the development of Wilms' tumour. The nephrectomy specimens demonstrated nephrogenic rests (nephroblastomatosis), which have a potential for malignant transformation. CONCLUSIONS: WT1 missense mutations in exons 8 and 9 can be regarded as having the potential for malignant change supporting prophylactic nephrectomy in apparent incomplete DDS patients with end-stage renal disease.

Child↗

PubMed2003

Differences in the predictive validity of actuarial risk assessments in relation to sex offender type.

This study seeks to expand on the previously reported validity of the Static-99, RRASOR, MnSOST-R, and SORAG in predicting sexual recidivism utilizing a regional sample of offenders. The predictive validity of each test was determined utilizing subgroups of the sample based on each offender's known offense history. The effectiveness of each instrument varied depending on offender type. The Static-99 and SORAG were both significantly predictive of sexual, violent, and any recidivism for extra-familial child molesters, and all four tests were predictive of violent or any recidivism in this subgroup. For incest offenders, all four tests were at least moderately predictive of sexual recidivism, whereas the Static-99 and the SORAG were highly predictive of violent or any recidivism. None of the four tests established consistent predictive validity across recidivism categories in regard to rapists or hands-off offenders, however, the Static-99 and the SORAG were significant in terms of sexual recidivism.

Actuarial Analysis↗

PubMed2003

Are social norms campaigns really magic bullets? assessing the effects of students' misperceptions on drinking behavior.

In an attempt to curb excessive drinking on college campuses, many universities have turned to "social norms" marketing campaigns. Despite widespread acceptance among health educators, empirical results are clouded by measurement problems. This study, based on a random sample of 550 students, examined the effects of misperceptions of friends' and typical college students' drinking on one's drinking behavior. Results indicate that drinking behavior is positively related to perceptions of friends' drinking as suggested by the theory of planned behavior, which emphasizes subjective as opposed to social norms.

Adolescent↗

PubMed2002

N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1 receptor.

In superior cervical ganglion neurons, N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) competitively antagonizes the Ca(2+) current effect of the cannabinoid (CB) agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), and behaves as an inverse agonist by producing opposite current effects when applied alone. In contrast, in neurons expressing CB1 with a K-->A mutation at residue 3.28(192) (i.e., K3.28A), SR141716A competitively antagonizes the effects of WIN55212-2, but behaves as a neutral antagonist by producing no current effects itself. Receptor modeling studies suggested that in the CB1 inactive (R) state, SR1417A16A stabilizes transmembrane helix 6 in its inactive conformation via aromatic stacking with F3.36/W6.48. In this binding site, SR141716A would exhibit higher affinity for CB1 R due to a hydrogen bond between the SR141716A C3 substituent and K3.28(192), a residue available to SR141716A only in R. To test this hypothesis, a "mutant thermodynamic cycle" was constructed that combined the evaluation of SR141716A affinity at WT CB1 and K3.28A with an evaluation of the wild-type CB1 and K3.28A affinities of an SR141716A analog, 5-(4-chlorophenyl)-3-[(E)-2-cyclohexylethenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole (VCHSR), that lacks hydrogen bonding potential at C3. Binding affinities suggested that K3.28 is involved in a strong interaction with SR141716A in WT CB1, but does not interact with VCHSR. Thermodynamic cycle calculations indicated that a direct interaction occurs between the C3 substituent of SR141716A and K3.28 in WT CB1. Consistent with these results, VCHSR acted as a neutral antagonist at WT CB1. These results support the hypothesis that hydrogen bonding of the SR141716A C3 substituent with K3.28 is responsible for its higher affinity for the inactive R state, leading to its inverse agonism.

Binding Sites↗

PubMedDate not supplied

Computers in patient education.

Nurses in practice have an increasing need to become aware of the computer-based resources available and the evidence regarding their use in the process of patient education. This synthesis of the literature examines research related to computer-based patient education. A particular focus is placed on the nurse clinician's perspective and the role of the nurse as a patient educator in the digital age. Two primary healthcare database resources, MEDLINE and CINAHL, were selected for review of the current literature. A listing of articles related to the use of computer technology in patient education was obtained from both of these databases. The search strategy included exploding the subject heading terms "computer" and "patient education," and included articles from 1971 to 2001. Computer-based patient education is an effective strategy for improving healthcare knowledge and clinical outcomes. Computer-based learning can be tailored to the individual's age and specific learning needs. Furthermore, although access to computer-based resources continues to be a barrier for some, socioeconomic disparities have no reported impact on patients' abilities to use computer-based technologies effectively.

Attitude to Computers↗

PubMedDate not supplied

Caring connection: developing an Internet resource for family caregivers of children with cancer.

This article describes the development of a family-focused Internet resource, the Caring Connection Web site, designed to provide individualized clinical information, patient-centered information, and access to online communication for caregivers of children with cancer. Data from surveys with family caregivers described the scope and characteristics of their current Internet use. Web site prototype development and user testing provided additional insights that inform the ongoing design of the Caring Connection Web site. The family caregivers and oncology healthcare providers who participated are active users of Internet health information. The preliminary data they provided support the feasibility and usability of the Caring Connection prototype. Ongoing development of the Caring Connection Web site will provide an innovative approach to assist these family caregivers in meeting currently unmet information and communication needs, and will provide evidence regarding "best practice" in design and development of Internet resources to support communication and information sharing.

Adult↗