Alex Ewing - Academia.edu (original) (raw)
Papers by Alex Ewing
International Journal of Cancer, 2008
Usual type VIN is a premalignant disorder caused by persistent HPV infection. High prevalence of ... more Usual type VIN is a premalignant disorder caused by persistent HPV infection. High prevalence of VIN in immuno-suppressed women suggests that a good innate and adaptive immune response is important for defense against HPV. Here, we explored expression levels of chemokines and related these to the presence or absence of immuno-competent cells (dendritic and T-cells) in affected (HPV-positive VIN) and non-affected (HPV-negative) vulvar tissues from the same patients. Combining microarray data with quantitative real-time RT-PCR, it was observed that several important chemokines were differentially expressed between VIN and control samples (up-regulation of IL8, CXCL10, CCL20 and CCL22 and down-regulation of CXCL12, CCL21 and CCL14). Furthermore, an increased number of mature dendritic cells (CD208+) seemed to be bottled up in the dermis, and although a T-cell response (increased CD4+ and CD8+ cells) was observed in VIN, a much larger response is required to clear the infection. In summary, it seems that most mature dendritic cells do not receive the proper chemokine signal for migration and will stay in the dermis, not able to present viral antigen to naive T-cells in the lymph node. Consequently the adaptive immune response diminishes, resulting in a persistent HPV infection with increased risk for neoplasia. © 2008 Wiley-Liss, Inc.
Chemical Physics, 1995
The mechanism for the reaction of atomic chlorine with vibrationally excited methane is investiga... more The mechanism for the reaction of atomic chlorine with vibrationally excited methane is investigated by measurement of correlated state and scattering distributions using the method of core extraction (see preceding paper). Laser photolysis of molecular chlorine creates monoenergetic chlorine atoms (≳98% Cl 2P3/2) that react with vibrationally excited methane molecules prepared by linearly polarized infrared laser excitation. The resulting HCl product population distributions are determined by (2+1) resonance-enhanced multiphoton ionization (REMPI), and the differential cross section for each product rovibrational state is measured by core extraction. Approximately 30% of the product is formed in HCl(υ=1,J) with a cold rotational distribution; the remaining population is formed in HCl(υ=0,J) and is more rotationally excited. We observe a rich variation of the scattered flux that is dependent on the internal-energy state of the product. The HCl(υ=1) product is sharply forward scattered for low J and becomes nearly equally forward-backward scattered for high J; the HCl(υ=0,J) product is back and side scattered. The reactions of Cl with C-H stretch-excited methane (CH4) and C-H stretch-excited CHD3 are found to have similar angular and internal-state distributions. Observation of the spatial anisotropy of the HCl(υ=0, J=3) product shows that significant vibrational excitation of the methyl fragment does not occur. The measured spatial anisotropy is most consistent with a model in which backscattered HCl(υ=0, J=3) is formed in coincidence with slight methyl vibrational excitation and the forward-scattered HCl(υ=0, J=3) is formed in coincidence with no methyl excitation. The approach of the attacking chlorine atom with respect to the C-H stretch direction can be varied by rotating the plane of polarization of the infrared excitation. A marked steric effect is observed in which Cl atoms approaching perpendicular to the C-H stretch preferentially yield forward-scattered HCl(υ=1) product. On the other hand, the reaction is weakly dependent on the rotational quantum state of CH4(υ3=1,J), and on the rotational polarization. The data are consistent with a model that has a widely open ``cone of acceptance'' in which the impact parameter controls the internal-state and scattering distributions of the HCl product.
Alternatives to surgery are needed for the treatment of vulvar intraepithelial neoplasia. We inve... more Alternatives to surgery are needed for the treatment of vulvar intraepithelial neoplasia. We investigated the effectiveness of imiquimod 5% cream, a topical immune-response modulator, for the treatment of this condition. Fifty-two patients with grade 2 or 3 vulvar intraepithelial neoplasia were randomly assigned to receive either imiquimod or placebo, applied twice weekly for 16 weeks. The primary outcome was a reduction of more than 25% in lesion size at 20 weeks. Secondary outcomes were histologic regression, clearance of human papillomavirus (HPV) from the lesion, changes in immune cells in the epidermis and dermis of the vulva, relief of symptoms, improvement of quality of life, and durability of response. Reduction in lesion size was classified as complete response (elimination), strong partial response (76 to 99% reduction), weak partial response (26 to 75% reduction), or no response (< or =25% reduction). The follow-up period was 12 months. Lesion size was reduced by more than 25% at 20 weeks in 21 of the 26 patients (81%) treated with imiquimod and in none of those treated with placebo (P<0.001). Histologic regression was significantly greater in the imiquimod group than in the placebo group (P<0.001). At baseline, 50 patients (96%) tested positive for HPV DNA. HPV cleared from the lesion in 15 patients in the imiquimod group (58%), as compared with 2 in the placebo group (8%) (P<0.001). The number of immune epidermal cells increased significantly and the number of immune dermal cells decreased significantly with imiquimod as compared with placebo. Imiquimod reduced pruritus and pain at 20 weeks (P=0.008 and P=0.004, respectively) and at 12 months (P=0.04 and P=0.02, respectively). The lesion progressed to invasion (to a depth of <1 mm) in 3 of 49 patients (6%) followed for 12 months (2 in the placebo group and 1 in the imiquimod group). Nine patients, all treated with imiquimod, had a complete response at 20 weeks and remained free from disease at 12 months. Imiquimod is effective in the treatment of vulvar intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN11290871 [controlled-trials.com].).
International Journal of Cancer, 2008
Usual type VIN is a premalignant disorder caused by persistent HPV infection. High prevalence of ... more Usual type VIN is a premalignant disorder caused by persistent HPV infection. High prevalence of VIN in immuno-suppressed women suggests that a good innate and adaptive immune response is important for defense against HPV. Here, we explored expression levels of chemokines and related these to the presence or absence of immuno-competent cells (dendritic and T-cells) in affected (HPV-positive VIN) and non-affected (HPV-negative) vulvar tissues from the same patients. Combining microarray data with quantitative real-time RT-PCR, it was observed that several important chemokines were differentially expressed between VIN and control samples (up-regulation of IL8, CXCL10, CCL20 and CCL22 and down-regulation of CXCL12, CCL21 and CCL14). Furthermore, an increased number of mature dendritic cells (CD208+) seemed to be bottled up in the dermis, and although a T-cell response (increased CD4+ and CD8+ cells) was observed in VIN, a much larger response is required to clear the infection. In summary, it seems that most mature dendritic cells do not receive the proper chemokine signal for migration and will stay in the dermis, not able to present viral antigen to naive T-cells in the lymph node. Consequently the adaptive immune response diminishes, resulting in a persistent HPV infection with increased risk for neoplasia. © 2008 Wiley-Liss, Inc.
Chemical Physics, 1995
The mechanism for the reaction of atomic chlorine with vibrationally excited methane is investiga... more The mechanism for the reaction of atomic chlorine with vibrationally excited methane is investigated by measurement of correlated state and scattering distributions using the method of core extraction (see preceding paper). Laser photolysis of molecular chlorine creates monoenergetic chlorine atoms (≳98% Cl 2P3/2) that react with vibrationally excited methane molecules prepared by linearly polarized infrared laser excitation. The resulting HCl product population distributions are determined by (2+1) resonance-enhanced multiphoton ionization (REMPI), and the differential cross section for each product rovibrational state is measured by core extraction. Approximately 30% of the product is formed in HCl(υ=1,J) with a cold rotational distribution; the remaining population is formed in HCl(υ=0,J) and is more rotationally excited. We observe a rich variation of the scattered flux that is dependent on the internal-energy state of the product. The HCl(υ=1) product is sharply forward scattered for low J and becomes nearly equally forward-backward scattered for high J; the HCl(υ=0,J) product is back and side scattered. The reactions of Cl with C-H stretch-excited methane (CH4) and C-H stretch-excited CHD3 are found to have similar angular and internal-state distributions. Observation of the spatial anisotropy of the HCl(υ=0, J=3) product shows that significant vibrational excitation of the methyl fragment does not occur. The measured spatial anisotropy is most consistent with a model in which backscattered HCl(υ=0, J=3) is formed in coincidence with slight methyl vibrational excitation and the forward-scattered HCl(υ=0, J=3) is formed in coincidence with no methyl excitation. The approach of the attacking chlorine atom with respect to the C-H stretch direction can be varied by rotating the plane of polarization of the infrared excitation. A marked steric effect is observed in which Cl atoms approaching perpendicular to the C-H stretch preferentially yield forward-scattered HCl(υ=1) product. On the other hand, the reaction is weakly dependent on the rotational quantum state of CH4(υ3=1,J), and on the rotational polarization. The data are consistent with a model that has a widely open ``cone of acceptance'' in which the impact parameter controls the internal-state and scattering distributions of the HCl product.
Alternatives to surgery are needed for the treatment of vulvar intraepithelial neoplasia. We inve... more Alternatives to surgery are needed for the treatment of vulvar intraepithelial neoplasia. We investigated the effectiveness of imiquimod 5% cream, a topical immune-response modulator, for the treatment of this condition. Fifty-two patients with grade 2 or 3 vulvar intraepithelial neoplasia were randomly assigned to receive either imiquimod or placebo, applied twice weekly for 16 weeks. The primary outcome was a reduction of more than 25% in lesion size at 20 weeks. Secondary outcomes were histologic regression, clearance of human papillomavirus (HPV) from the lesion, changes in immune cells in the epidermis and dermis of the vulva, relief of symptoms, improvement of quality of life, and durability of response. Reduction in lesion size was classified as complete response (elimination), strong partial response (76 to 99% reduction), weak partial response (26 to 75% reduction), or no response (< or =25% reduction). The follow-up period was 12 months. Lesion size was reduced by more than 25% at 20 weeks in 21 of the 26 patients (81%) treated with imiquimod and in none of those treated with placebo (P<0.001). Histologic regression was significantly greater in the imiquimod group than in the placebo group (P<0.001). At baseline, 50 patients (96%) tested positive for HPV DNA. HPV cleared from the lesion in 15 patients in the imiquimod group (58%), as compared with 2 in the placebo group (8%) (P<0.001). The number of immune epidermal cells increased significantly and the number of immune dermal cells decreased significantly with imiquimod as compared with placebo. Imiquimod reduced pruritus and pain at 20 weeks (P=0.008 and P=0.004, respectively) and at 12 months (P=0.04 and P=0.02, respectively). The lesion progressed to invasion (to a depth of <1 mm) in 3 of 49 patients (6%) followed for 12 months (2 in the placebo group and 1 in the imiquimod group). Nine patients, all treated with imiquimod, had a complete response at 20 weeks and remained free from disease at 12 months. Imiquimod is effective in the treatment of vulvar intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN11290871 [controlled-trials.com].).