The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression ...of several types of human malignancies. The best characterized of these proteins are the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-3,4-d-pyrimidine small molecules that are dual inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 microM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per day. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophosphorylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.
Abstract Objective To evaluate the presentation, treatments and outcomes in pediatric patients with salivary gland malignancies. Study design Retrospective chart review (1950-2012), Prospective phone ...interview. Methods Patients ≤ 18 years old with a salivary gland malignancy treated at our institution were identified. Patients were also contacted by phone for a follow up survey. Results Fifty-six patients were identified. Tumor origin was 88% parotid (n=49), 5% (n=3) submandibular and 7% (n=4) minor salivary glands. Time from onset of symptoms to diagnosis was over one year (mean=14.4 years). Fifteen out of 52 patients with major gland malignancy had a locoregional recurrence and local recurrences were almost all after initial enucleation. Two of these patients died of disease (overall disease specific survival=96%). Three out of 4 patients with minor gland malignancy had a local recurrence and two patients with high grade pathology developed metastases and died of their disease (overall survival=50%). On long term follow up survey in 13 patients (25%), 100% reported normal facial movement and 54% described symptoms of Frey’s syndrome, which is higher than other reported series in children. Recurrence was noted up to 45 years after initial treatment. Conclusions The majority of malignant pediatric salivary gland tumors are low grade and have excellent survival, especially if found at an early stage. Minor salivary gland malignancies, particularly high grade, have a worse prognosis. Long term mild Frey’s syndrome can be expected in approximately half of patients. We advocate a need for long term follow up and increased awareness among providers to diagnose these patients earlier.
OBJECTIVE Vertebral deformity is associated with back pain and disability. The aim of this analysis was to determine whether location within the spine influences the strength of association between ...vertebral deformity, back pain and disability. METHODS Men and women aged 50 years and over were recruited from population registers in 30 European centres. Subjects were invited for an interviewer administered questionnaire, and for lateral spinal radiographs. The questionnaire included questions about back pain, general health and functional ability. The spinal radiographs were evaluated morphometrically and vertebral deformity defined according to the McCloskey-Kanis method. RESULTS 756 (11.7%) men and 885 (11.8%) women had evidence of one or more vertebral deformities. Among women with a single deformity, after adjusting for age and centre, those with a lumbar deformity were more likely than those with a thoracic deformity to report back pain, both currently (OR=1.4; 95% CI 1.0, 2.0) and in the past year (OR=1.5; 95% CI 1.0, 2.3). No association was observed in men. Among women with two deformities, those with adjacent deformities were more likely than those with non-adjacent deformities to report poor general health (OR=2.2; 95%CI 0.9, 5.6), impaired functional ability (OR=1.9; 95%CI 0.8, 4.7) and current back pain (OR=2.1; 95%CI 0.9, 4.9), though none of these associations were statistically significant. By contrast, among men, non-adjacent deformities were associated with impaired functional ability compared with those with adjacent deformities. CONCLUSION Location within the spine influences the strength of association between self reported health factors and vertebral deformity.
Objective: To formulate diagnostic criteria for exercise dependence. Method: Fifty six adult female exercisers were interviewed about their exercise behaviour and attitudes. The eating disorders ...examination, a semistructured clinical interview, was used to diagnose eating disorders. Interviews were taped, transcribed verbatim, and analysed from a social constructionist perspective using QSR NUD*IST. Participants also completed the exercise dependence questionnaire. Results: Two diagnostic criteria emerged from analysis of the interview data: impaired functioning and withdrawal. Impaired functioning was manifest in four areas: psychological, social and occupational, physical, and behavioural. Impairment in at least two areas was considered necessary for diagnosis. Withdrawal was evident as either an adverse reaction to the interruption of exercise or unsuccessful attempts at exercise control. Either sufficed for diagnosis. The absence or presence of an eating disorder was used to distinguish between primary and secondary exercise dependence. Ten women met these criteria for exercise dependence. All 10 also exhibited eating disorders and, accordingly, should be regarded as showing secondary, rather than primary, exercise dependence. Exercise dependent women had significantly higher scores on the exercise dependence questionnaire than non-dependent women. Conclusion: These new diagnostic criteria should now be adopted and explored further, particularly among men and individuals with possible primary exercise dependence.
The advent of 'genomics' technology, in particular transcript profiling, has already had a measurable impact on the drug discovery process in the areas of target identification and validation. This ...review is concerned with the potential application of this technology to toxicology and drug safety assessment, with particular emphasis on biomarker discovery and characterization. An advantage (or possibly a drawback!) of transcript profiling is that candidate biomarkers of toxicity can be speedily identified, with the caveat that a significant amount of subsequent experimental and bioinformatic effort needs to be expended in order to evaluate and validate them. Attention is also drawn to the critical need for robust experimental design with studies of this type and to issues associated with the analysis of large data sets. In summary, while genomics technology undoubtedly offers much that can assist drug safety assessment, its potential has yet to be realized fully in this area. However, a large amount of resource continues to be applied to 'toxicogenomics'. Tangible benefits, in terms of new biomarkers of toxicity and reduced numbers of adverse drug effects, remain realistic objectives.
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