Correction to "Cellular Context Influences Kinase Inhibitor Selectivity".
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Published Erratum↗
Biomedical subjects
Michael Slater
Publications and source records attributed to Michael Slater.
Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products.
Vitamin D is produced in skin by UVB radiation (290-320 nm) acting on 7-dehydrocholesterol. The hypotheses that the active vitamin D hormone, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), would increase the survival of skin cells after UV irradiation and that surviving cells after 1,25(OH)2D3 treatment would have no increase in DNA damage were tested. The survival of keratinocytes post-UVR was significantly greater after treatment with 1,25(OH)2D3 compared to vehicle (P<0.01). Significant reductions in thymine dimers (TDs) in surviving keratinocytes after UVR were noted in the presence of 1,25(OH)2D3 (P<0.001). Nuclear p53 protein expression increased after UVR and was significantly higher in keratinocytes treated with 1,25(OH)2D3 (P<0.01), whereas NO products were significantly reduced (P<0.05). Both the increase in nuclear accumulation of p53 protein and reduced formation of nitric oxide products may contribute to the reduction in TDs seen with 1,25(OH)2D3 after UVR. Reductions in numbers of sunburn cells (P<0.01) and in TDs (P<0.05) were observed 24 hours after UVR in skin sections from Skh:hr1 mice treated with 1,25(OH)2D3. These results are consistent with the proposal that the vitamin D system in skin may be part of an intrinsic protective mechanism against UV damage.
Animals↗
"Click chemistry" in the preparation of porous polymer-based particulate stationary phases for mu-HPLC separation of peptides and proteins.
With the use of the copper(I)-catalyzed (3 + 2) azide-alkyne cycloaddition, an element of "click chemistry," stationary phases carrying long alkyl chains or soybean trypsin inhibitor have been prepared for use in HPLC separations in the reversed-phase and affinity modes, respectively. The ligands were attached via a triazole ring to size monodisperse porous beads containing either alkyne or azide pendant functionalities. Alkyne-containing beads prepared by direct copolymerization of propargyl acrylate with ethylene dimethacrylate were allowed to react with azidooctadecane to give a reversed-phase sorbent. Azide-functionalized beads were prepared by chemical modification of glycidyl methacrylate particles. Subsequent reaction with a terminal aliphatic alkyne produced a reversed-phase sorbent similar to that obtained from the alkyne beads. Soybean trypsin inhibitor was functionalized with N-(4-pentynoyloxy)succinimide to carry alkyne groups and then allowed to react with the azide-containing beads to produce an affinity sorbent for trypsin. The performance of these stationary phases was demonstrated with the HPLC separations of a variety of peptides and proteins.
Alkynes↗
Human growth hormone and interleukin-6 are upregulated in endometriosis and endometrioid adenocarcinoma.
In this retrospective and quantitated study on banked tissue we found that, compared to normal uterine epithelial cells, growth hormone (GH) is increased 3.4-fold in endometriosis and 3.8-fold in endometrial adenocarcinoma. Similarly, interleukin-6 (IL-6) is increased 2.4-fold in endometriosis and 4.4-fold in endometrial adenocarcinoma. These proteins appear to be involved in the progression of both these conditions. GH is particularly interesting in this context since it is known to not only promote cellular proliferation but also reduces cell-cell adhesion, thus allowing individual cells to break away from their parent architecture. Our results suggest that both IL-6 and GH may play a role in the progression of both endometriosis and endometrial carcinoma.
Carcinoma, Endometrioid↗
Effects of alcohol advertising exposure on drinking among youth.
OBJECTIVE: To test whether alcohol advertising expenditures and the degree of exposure to alcohol advertisements affect alcohol consumption by youth. DESIGN: Longitudinal panel using telephone surveys. SETTING: Households in 24 US media markets, April 1999 to February 2001. PARTICIPANTS: Individuals aged 15 to 26 years were randomly sampled within households and households within media markets. Markets were systematically selected from the top 75 media markets, representing 79% of the US population. The baseline refusal rate was 24%. Sample sizes per wave were 1872, 1173, 787, and 588. Data on alcohol advertising expenditures on television, radio, billboards, and newspapers were collected. MAIN EXPOSURES: Market alcohol advertising expenditures per capita and self-reported alcohol advertising exposure in the prior month. MAIN OUTCOME MEASURE: Self-reported number of alcoholic drinks consumed in the prior month. RESULTS: Youth who saw more alcohol advertisements on average drank more (each additional advertisement seen increased the number of drinks consumed by 1% [event rate ratio, 1.01; 95% confidence interval, 1.01-1.02]). Youth in markets with greater alcohol advertising expenditures drank more (each additional dollar spent per capita raised the number of drinks consumed by 3% [event rate ratio, 1.03; 95% confidence interval, 1.01-1.05]). Examining only youth younger than the legal drinking age of 21 years, alcohol advertisement exposure and expenditures still related to drinking. Youth in markets with more alcohol advertisements showed increases in drinking levels into their late 20s, but drinking plateaued in the early 20s for youth in markets with fewer advertisements. Control variables included age, gender, ethnicity, high school or college enrollment, and alcohol sales. CONCLUSION: Alcohol advertising contributes to increased drinking among youth.
Adolescent↗
Expression of the apoptotic calcium channel P2X7 in the glandular epithelium.
In the current study, expression of the apoptotic calcium channel receptor P2X(7) and prostate-specific antigen (PSA) levels were studied in biopsy cores from 174 patients as well as 20 radical prostatectomy cases. In clinical biopsies, we have previously demonstrated that P2X(1 )and P2X(2) calcium channel receptors are absent from normal prostate epithelium that does not progress to prostate cancer within 5 years. In cases that did progress to prostate cancer however, P2X(1 )and P2X(2) labeling was observed in a stage-specific manner first in the nucleus, then the cytoplasm and finally on the apical epithelium, as prostate cancer developed. These markers were present up to 5 years before cancer was detectable by the usual morphological criteria (Gleason grading) as determined by H and E staining. In the current study, the apoptotic calcium channel receptor P2X(7) yielded similar results to that of P2X(1) and P2X(2). Using radical prostatectomy tissue sections as well as biopsies, these changes in calcium channel metabolism were noted throughout the prostate, indicating a field effect. This finding suggests that the presence of a prostate tumor could be detected without the need for direct sampling of tumor tissue, leading to detection of false negative cases missed by H or E stain. The reliability of PSA levels as a prognostic indicator has been questioned in recent years. In the current study, PSA levels were correlated with the P2X(7) labeling results. All patients who exhibited no P2X(7) labeling had a prostatic serum antigen (PSA) level of <2. Patients who exhibited stage-specific P2X(7) expression, and who later developed obvious prostate cancer as diagnosed by H and E stain, all had a PSA > 2. This finding suggests that increasing PSA may be an accurate indicator of cancer development.
Aged↗
Differentiation between cancerous and normal hyperplastic lobules in breast lesions.
Determining the risk that a particular area of hyperplastic breast tissue will progress to cancer is difficult and is currently expressed only as a general risk factor within the population. Using an antibody against the apoptotic purinergic receptor P2X7, we examined 40 cases each of the following histological categories: normal, moderate, florid and atypical hyperplasia, lobular carcinoma in situ, ductal carcinoma in situ, invasive lobular and invasive ductal carcinoma. These were previously diagnosed by H&E and supplied by clinical laboratories as tissue sections. Normal and mildly hyperplastic epithelium was devoid of the cytolytic P2X7 receptors whereas all epithelial cells in all cases of in situ or invasive lobular or ductal carcinoma labelled intensely. The lobular and ductal in situ cases labelled intracellularly while the invasive epithelial cancer cells showed intense cell surface label indicating an attempt was being made to induce apoptosis. All these receptors however are non-functional and thus unable to induce apoptosis. Approximately 10% of all hyperplastic lobules examined in the biopsied tissue, regardless of H&E classification, labelled for P2X7, which is suggestive of early metabolic cancerous change. The acini within lobules were either completely labelled with P2X7 or were completely devoid of the receptor. A potential advantage of this method lies in identifying early cancerous change in hyperplastic lobules and in establishing the true extent of cancerous spread in infiltrating lesions, thus facilitating the task of reporting clear surgical margins.
Breast↗
Increased expression of apoptotic markers in melanoma.
Extensive labelling for the apoptotic markers calcium channel receptor P2X(7) and caspase-3 and telomerase activity was co-localized at a similar intensity in areas affected by superficial spreading melanoma obtained from 80 patients. Labelling for each of these markers also extended 2 microm from the melanoma into the keratinocyte layer of the adjacent normal epidermis. Conversely, the calcium-regulating receptors P2X(1-3) and P2Y(2) (found in normal but not neoplastic skin) were fully de-expressed within 2 microm of the melanoma but fully expressed beyond that distance. The cell adhesion protein E-cadherin (also only present in normal skin) was progressively de-expressed from a point 2 microm from the melanoma until full de-expression within the lesion. These results show that telomerase-induced proliferation and defensive apoptosis are co-localized and simultaneous processes in melanoma tissue. Melanoma cell proliferation appears to overwhelm the apoptotic defence, perhaps due to the anti-apoptotic effects of telomerase. In addition, keratinocyte regulation of the epidermis and dermis is severely compromised by the loss of E-cadherin and P2X(1-3) and P2Y(2) receptors, resulting in a lesion that is aggressive and malignant.
Apoptosis↗
Purinergic receptor distribution in endothelial cells in blood vessels: a basis for selection of coronary artery grafts.
Expression levels of the purinergic P2X receptor subunits (P2X(1) to P2X(7)) and P2Y(2) were examined in the endothelial cell layer of internal mammary artery (Ann. Thorac. Surg. 54 (1992) 652), radial artery (Ann. Thorac. Surg. 16 (1973) 111) and saphenous vein (Ann. Thorac. Surg. 20 (1975) 628) samples obtained at surgery for coronary artery bypass grafts using immunohistochemistry and confocal microscopy. Similar levels of P2X(1), P2X(2), P2X(3), P2X(7) and P2Y(2) were found in the endothelial cells in all vessels examined while the levels of P2X(5) and P2X(6) were uniformly lower. A clear difference was measured in P2X(4) expression between arteries and veins. Both radial and internal mammary arteries exhibited very low levels of P2X(4) whereas the level in the saphenous vein was 14.6 fold higher (P<0.0001), approaching that of the major receptor subtypes. These data showing strong expression of P2X(4) in veins have implications for the choice of vessels used in coronary artery bypass grafts given that P2X(4) is involved in calcium influx into endothelial cells, modulates blood vessel contractility and is up-regulated in situations involving intima proliferation suggesting vein grafts are more susceptible to developing atherosclerosis.
Antibody Specificity↗
Perceptions of dietary supplements among older women with diabetes.
PURPOSE: The purpose of this qualitative study was to explore the meaning of taking dietary supplements from the perspective of being an older woman with type 2 diabetes. METHODS: Nine women over the age of 65 with type 2 diabetes participated in a single, in-depth semistructured interview that focused on use of, views of, and methods of hearing about supplements. Interviews were audiotaped, transcribed verbatim, and analyzed using phenomenological methodology. RESULTS: Eight of the 9 participants used some form of dietary supplement daily. Respondents described methods of hearing about supplements ranging from their daughters to the media to "people talk." Individual supplements were used primarily to prevent or treat conditions related to aging, such as osteoporosis, arthritis, and vision loss. They were also taken to prevent or lessen conditions associated with diabetes, including heart disease. CONCLUSIONS: The older women with type 2 diabetes in this study used dietary supplements. However, taking supplements was not perceived as a means of controlling blood glucose and, as such, supplements were not taken as part of their diabetes treatment regimen.
Aged↗
Radiation sources providing increased UVA/UVB ratios induce photoprotection dependent on the UVA dose in hairless mice.
In studies involving mice in which doses of UVA (320-400 nm) and UVB (290-320 nm) radiation were administered alone or combined sequentially, we observed a protective effect of UVA against UVB-induced erythema/edema and systemic suppression of contact hypersensitivity. The UVA immunoprotection was mediated by the induction of the stress enzyme heme oxygenase-1 (HO-1) in the skin, protection of the cutaneous Th1 cytokines interferon-gamma (IFN-gamma) and IL-12 and inhibition of the UVB-induced expression of the Th2 cytokine IL-10. In this study, we seek evidence for an immunological waveband interaction when UVA and UVB are administered concurrently to hairless mice as occurs during sunlight exposure in humans. A series of spectra providing varying ratios of UVA/UVB were developed, with the UVA ratio increased to approximately 3.5 times the UVA component in solar simulated UV (SSUV). We report that progressively increasing the UVA component of the radiation while maintaining a constant UVB dose resulted in a reduction of both the erythema/edema reaction and the degree of systemic immunosuppression, as measured as contact hypersensitivity. The UVA-enhanced immunoprotection was abrogated in mice treated with a specific HO enzyme inhibitor. UVA-enhanced radiation also upregulated the expression of cutaneous IFN-gamma and IL-12 and inhibited expression of both IL-6 and IL-10, compared with the activity of SSUV. The results were consistent with the previously characterized mechanisms of photoprotection by the UVA waveband alone and suggest that the UVA component of solar UV may have beneficial properties for humans.
Animals↗