Identification of a transiently exposed VE-cadherin epitope that allows for specific targeting of an antibody to the tumor neovasculature

VE-cadherin is an adhesion molecule localized at the adherens junctions of endothelial cells. It is crucial for the proper assembly of vascular structures during angiogenesis and maintaining vascular integrity. We have studied 3 monoclonal antibodies (mAbs) against murine VE-cadherin that inhibit angiogenesis and tumor growth. Two of these, BV13 and 10G4, also disrupted normal vessels, resulting in severe vascular leakage, whereas the third, E4G10, did not. The goal of the current report was to identify the epitope of E4G10 and distinguish it from those of the disruptive mAbs. We mapped the epitope of E4G10 to within the first 10 amino acids of mature VE-cadherin and demonstrated that conserved tryptophan residues in this sequence are required for VE-cadherin-mediated trans-adhesion. The disruptive mAbs target a different epitope within amino acids 45 to 56, which structural homology modeling suggests is not involved in trans-adhesion. From our studies, we hypothesize that E4G10 can only bind the neovasculature, where VE-cadherin has not yet engaged in trans-adhesion and its epitope is fully exposed. Thus, E4G10 can inhibit junction formation and angiogenesis but is unable to target normal vasculature because its epitope is masked. In contrast, BV13 and 10G4 bind an epitope that is accessible regardless of VE-cadherin interactions, leading to the disruption of adherens junctions. Our findings establish the immediate N-terminal region of VE-cadherin as a novel target for inhibiting angiogenesis.     

Nonmelanoma skin cancer in relation to ionizing radiation exposure among U.S. radiologic technologists

Ionizing radiation (IR) is an established cause of nonmelanoma skin cancer, but there is uncertainty about the risk associated with chronic occupational exposure to IR and how it is influenced by ultraviolet radiation (UVR) exposure. We studied 1,355 incident cases with basal cell carcinoma (BCC) and 270 with squamous cell carcinoma (SCC) of the skin in a cohort of 65,304 U.S. white radiologic technologists who responded to the baseline questionnaire survey in 1983-1989 and the follow-up survey in 1994-1998. Cox's proportional-hazards model was used to estimate relative risks of BCC and SCC associated with surrogate measures of occupational exposure to IR and residential UVR exposure during childhood and adulthood, adjusted for potential confounders including pigmentation characteristics. Relative risks of BCC, but not of SCC, were elevated among technologists who first worked during the 1950s (RR = 1.42; 95% CI = 1.12-1.80), 1940s (RR = 2.04; 95% CI = 1.44-2.88) and before 1940 (RR = 2.16; 95% CI = 1.14-4.09), when IR exposures were high, compared to those who first worked after 1960 (p for trend < 0.01). The effect of year first worked on BCC risk was not modified by UVR exposure, but was significantly stronger among individuals with lighter compared to darker eye and hair color (p = 0.013 and 0.027, respectively). This study provides some evidence that chronic occupational exposure to IR at low to moderate levels can increase the risk of BCC, and that this risk may be modified by pigmentation characteristics.     

Use of recombinant human chorionic gonadotropin in ovulation induction

To review the use of hCG and to describe the clinical benefit of recombinant hCG (r-hCG) based on the published results of prospective, randomized studies.Review of published articles.Tertiary infertility care center.None.None.Oocyte number and quality, luteal phase progesterone, pregnancy and OHSS rate, and local tolerability.The published data consistently show that single doses of 250 microg r-hCG and 5,000 IU urinary (u)-hCG produce similar clinical outcomes when used in infertility treatment cycles for timed intercourse, IUI, and IVF in terms of the number of oocytes retrieved, number of mature oocytes harvested, and fertilization and pregnancy rates attained. Single doses of 10,000 IU u-hCG also gave results comparable to single doses of 250 microg r-hCG. P levels in the midluteal phase were significantly higher with the use of r-hCG compared with u-hCG, and local injection site adverse effects were significantly less frequent, demonstrating the higher purity of the recombinant product. A single 500-microg dose of r-hCG led to a higher rate of ovarian hyperstimulation syndrome compared with a 250-microg dose, with no significant improvement in pregnancy rates.A single dose of 250 microg r-hCG was at least as effective as single doses of 5,000 or 10,000 IU u-hCG but offered the advantages associated with use of a recombinant product: local injection site adverse effects were significantly less frequent with r-hCG than with u-hCG.     

Changes in the phenotype of T-cell subset determinants following murine cytomegalovirus infection

The murine model provides a particularly apt experimental system in which to evaluate the effects of cytomegalovirus (CMV) infection. CMV exerts a profound "suppression" of the immune response in the mouse and in humans; the infected animal is no longer able to mediate an appropriate response to mitogens or alloantigens. Using fluorocytometry and fluoresceinated monoclonal antibodies directed against the Thy-1.2, Lyt-1, and Lyt-2 cell membrane determinants following a nonlethal intraperitoneal inoculation of weanling BALB/c mice with Smith strain murine cytomegalovirus, significant changes in T-cell subsets were found that are consistent with findings described in the clinical situation. These ratio changes are temporally consistent with the cytotoxic T-lymphocyte population described by others. Finally, novel changes in the antigenic determinant distribution is found which may reflect the appearance of an antigen-committed cytotoxic T-lymphocyte population. This population which peaks at the ninth postinfection day may consist of 20-47% of the T-lymphocyte population and may offer an explanation for the cellular hyporesponsiveness seen following CMV infection.     

Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals

Two potential breast cancer susceptibility genes, encoding the BRCA1-interacting proteins ZNF350 (or ZBRK1) and BRIP1 (or BACH1), have been identified in yeast two-hybrid screens. We sequenced these genes in probands from 21 families with potentially inherited breast/ovarian cancer, all of which were negative for BRCA1/BRCA2 mutations. Families had at least one case of male breast cancer, two cases of ovarian cancer, or three or more cases of breast and ovarian cancer. In addition, 58 early-onset (before age 35) breast cancer cases and 30 reference individuals were analyzed. Of 17 variants detected in ZBRK1, a missense mutation Val524Ile was identified in the proband of one high-risk family, but no other family members were available for testing. Of 25 variants identified in BRIP1, in addition to four common silent or missense mutations, we identified Gln540Leu, a non-conservative amino acid change, in a single familial proband with inflammatory breast cancer, but this mutation was not present in her three relatives with breast cancer. Haplotype analysis suggests that all ZBRK1 SNPs fall within a single block with two SNPs capturing 92% of the haplotype diversity, while the BRIP1 SNPs fall in two blocks, with five SNPs capturing 89% of the haplotype diversity. Based on sequencing of ZBRK1 and BRIP1 in 21 BRCA1/2-negative probands from inherited breast/ovarian cancer families, it appears unlikely that mutations in these genes account for a significant fraction of inherited breast cancer. Further analysis in unselected cases will be required to know whether the identified variants play a role in genetic predisposition to breast cancer in the general population. Hum Mutat 22:121-128, 2003. Published 2003 Wiley-Liss, Inc.     

Lung cancer mortality associated with protracted low-dose occupational radiation exposures and smoking behaviors in U.S. radiologic technologists, 1983-2012

In the Japanese atomic bomb survivors, risk of lung cancer has been shown to increase with greater acute exposure to ionizing radiation. Although similar findings have been observed in populations exposed to low-dose, protracted radiation, such studies lack information on cigarette smoking history, a potential confounder. In a cohort of 106 068 U.S. radiologic technologists, we examined the association between estimated cumulative lung absorbed dose from occupational radiation exposure and lung cancer mortality. Poisson regression models, adjusted for attained age, sex, birth cohort, pack-years smoked and years since quitting smoking, were used to calculate linear excess relative risks (ERR) per 100 mGy, using time-dependent cumulative lung absorbed dose, lagged 10 years. Mean cumulative absorbed dose to the lung was 25 mGy (range: 0-810 mGy). During the 1983 to 2012 follow-up, 1090 participants died from lung cancer. Greater occupational radiation lung dose was not associated with lung cancer mortality overall (ERR per 100 mGy: −0.02, 95% CI: <0-0.13). However, significant dose-response relationships were observed for some subgroups, which might be false-positive results given the number of statistical tests performed. As observed in other studies of radiation and smoking, the interaction between radiation and smoking appeared to be sub-multiplicative with an ERR per 100 mGy of 0.41 (95% CI: 0.01-1.15) for those who smoked <20 pack-years and −0.03 (95% CI: <0-0.15) for those who smoked ≥20 pack-years. Our study provides some evidence that greater protracted radiation exposure in the low-dose range is positively associated with lung cancer mortality.     

Phytoestrogen exposure is associated with circulating sex hormone levels in postmenopausal women and interact with ESR1 and NR1I2 gene variants.

In this large cross-sectional study, we investigated the relationship between phytoestrogen exposure and circulating sex hormones and sex hormone-binding globulin (SHBG) levels in 1988 healthy postmenopausal women and their interactions with polymorphisms in genes involved in estrogen signaling. Plasma estradiol, testosterone, androstenedione, estrone, and SHBG were measured. Urinary levels of five isoflavones (daidzein, genistein, glycitein, O-desmethylangolensin, and equol) and two lignans (enterodiol and enterolactone) were measured and used as biomarkers for dietary intakes. Eighteen polymorphisms in ESR1, ESR2, and NR1I2 genes were genotyped. Results showed that lignans were positively associated with plasma SHBG levels (eta(p)(2) = 1.2%; P < 0.001) and negatively associated with plasma testosterone (eta(p)(2) = 0.2%; P = 0.042). Equol was negatively associated with plasma estradiol levels (eta(p)(2) = 0.3%; P = 0.028), whereas O-desmethylangolensin was positively associated with plasma estradiol level (eta(p)(2) = 0.3%; P = 0.010). There were significant phytoestrogen interactions with polymorphisms in ESR1 and NR1I2 genes in affecting estrone levels. We conclude that phytoestrogens modulate sex hormone and SHBG levels in postmenopausal women and interact with gene variants involved in estrogen signaling. Such phytoestrogen-gene interactions may explain the conflicting literature on the hormonal effects of phytoestrogens.     

The Alzheimer's Disease Assessment Scale-Cognitive subscale: normative data for older adult controls

The Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog) is commonly used to assess cognitive dysfunction in individuals with Alzheimer disease and other dementias. The purpose of this study was to provide normative scores for the ADAS-cog 11 individual items and total score, as well for delayed recall errors, using normal, elderly volunteers. The ADAS-cog was administered to 124, non-cognitively impaired volunteers ages 55 to 89, with 10 to 21 years of education. The mean total ADAS-cog score was five. The ADAS-cog error score was not associated with education in this highly educated group, and was positively correlated (P < 0.001) with the age of the participant. Age stratified ADAS-cog normative data are reported for the ADAS-cog total and the delayed recall error score.