Antibodies to PAI-1 alter the invasive and migratory properties of human tumour cells in vitro

Recent reports suggest that elevated levels of plasminogen activator inhibitor-1 (PAI-1) may contribute to tumour progression. The studies reported here were designed to help elucidate PAI-1's contribution to the invasive and migratory phenotype. Antibodies to PAI-1 dose-dependently, and significantly, inhibited the invasive and migratory potential of human HT1080 fibrosarcoma cells, as did an antibody to uPA and the plasmin inhibitor aprotinin. Invasion of the human melanoma cell line, BLM, was also attenuated by the anti-PAI-1 monoclonal antibody MAI-12. The non-invasive human melanoma cell line, IF6, which does not express uPA, provided further confirmation of PAI-1 and uPA's role as, upon transfection with uPA, this cell line attained an invasive phenotype, which was again attenuated by MAI- 12. Although antibodies to PAI-1 did not affect the adhesion of HT1080 cells to vitronectin, the antibody to uPA reduced their attachment. Addition of exogenous PAI-1, however, prevented HT1080 cell adhesion (IC₅₀ 180nM) and promoted cell detachment from vitronectin. Furthermore melanoma cells transfected with a uPA variant, which had an impaired interaction with PAI-1, were not invasive and had impaired binding to vitronectin. These data highlight the importance of a balanced proteolysis and suggest an additional role for PAI-1 distinct from its role in proteolysis. These data also suggest that uPA and PAI-1 may co-operate in the migratory process by respectively facilitating the attachment to, and subsequent detachment from, vitronectin in the extracellular matrix. These results support the clinical findings and indicate that modulation of PAI-1 activity may be of therapeutic benefit for the treatment of cancer. This revised version was published online in July 2006 with corrections to the Cover Date.     

Accuracy of family history of cancer: clinical genetic implications

Family medical history is the cornerstone of clinical genetic diagnosis and management in cases of familial cancer. The soundness of medical decisions can be compromised if reports by the family on affected relatives are inaccurate. Although very time consuming, family medical histories are therefore routinely verified. To investigate whether such verification is clinically justified, we retrospectively analysed the accuracy of a consecutive series of 383 tumour reports from counsellees on 120 families in our clinic. We evaluated these families for the impact of verification on clinical genetic diagnosis and management. Accuracy according to cancer type showed marked variation, ranging from 93% and 89% for breast cancer and colorectal cancer, respectively, to 42% and 37% for extra-colorectal alimentary tract cancer and uterine cancer. Accuracy was related to the degree of kinship of the affected relative, but not to age and gender of the counsellee, nor to the reason for referral or personal history of cancer. Age at diagnosis and multiple primary tumours were reported accurately in 97% and 94% of cases, respectively. In six out of 120 families verification data changed clinical genetic management, in five of these the genetic risk was reduced. Although verification of all reported cancer cases in a family remains the 'gold standard' for clinical as well as research purposes, verification of reports on breast cancer can be limited without seriously compromising medical decision making. In cases where verification is impossible because medical records are unavailable, findings from studies such as ours may help in interpreting family histories.     

Additional information from parental questionnaires and pharmacy records for registration of birth defects

EUROCAT Northern Netherlands registers children born with a birth defect in the Northern Netherlands. Data used to be collected via a notification form, which is filled out by the notifier and, if necessary, completed by the general practitioner. To increase the amount of information, EUROCAT started using new methodology in July 1997. The new procedure consists of three additional steps. Firstly, a parental questionnaire with 43 questions concerning pregnancy and medical history is sent to the parents. Also, the pharmacist is approached to provide information on the drugs that were dispensed to the mother in the period from three months before until the end of the pregnancy. The last step is a telephone interview with the mother. In this study the old and new method are compared with respect to response, quality and quantity of the data. Of the 198 parental questionnaires included in this study, 179 (90.4%) were returned. The pharmacists returned 173 out of 179 requests for information (96.6%). The parental information is more complete for ethnicity and serum screening. The quality of the drug exposure data is much better using the new methodology. The general practitioner's input is still necessary for specification and verification of the diagnosis.     

Maternal exposure to tobacco smoke, alcohol and caffeine, and risk of anorectal atresia: National Birth Defects Prevention Study 1997–2003

Anorectal atresia is a congenital anomaly with mostly unknown risk factors. Studies have provided evidence of teratogenic effects of alcohol and tobacco, and animal studies have suggested that caffeine may potentiate their teratogenicity. However, it is unclear how these factors affect the risk of anorectal atresia. We analysed data from maternal telephone interviews in a multistate case-control study with 464 infants with anorectal atresia and 4940 infants with no major birth defects. We used unconditional logistic regression to determine the association of exposure to smoking, environmental tobacco smoke (ETS), alcohol or caffeine with anorectal atresia. Effect modification by caffeine intake was assessed on additive and multiplicative scales.
There was no association with alcohol intake in this analysis. However, there was some evidence of an association between anorectal atresia and maternal exposure to tobacco smoke and caffeine. Compared with non-smokers not exposed to ETS, the crude odds ratio (OR) and 95% confidence interval [CI] for cigarette smoking was 1.2 [95% CI 1.0, 1.5]. The association with anorectal atresia for non-smokers exposed to ETS at home and work was OR = 2.3 [95% CI 1.2, 4.1]. Compared with the lowest level of caffeine intake (<10 mg/day), the association for the highest caffeine intake (≥300 mg/day) was OR = 1.5 [95% CI 1.0, 2.2]. Results did not change after adjustment for covariates. This study found evidence of associations between anorectal atresia and caffeine intake, cigarette smoking and exposure to ETS. Because there are currently few additional data to support these results, further study is needed.     

Maternal occupational exposure to polycyclic aromatic hydrocarbons: effects on gastroschisis among offspring in the National Birth Defects Prevention Study

Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) occurs in many occupational settings. There is evidence in animal models that maternal exposure to PAHs during pregnancy is associated with gastroschisis in offspring; however, to our knowledge, no human studies examining this association have been conducted.Objective: Our goal was to conduct a case–control study assessing the association between estimated maternal occupational exposure to PAHs and gastroschisis in offspring.Methods: Data from gastroschisis cases and control infants were obtained from the population-based National Birth Defects Prevention Study for the period 1997–2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to determine the association between estimated occupational PAH exposure and gastroschisis among children whose mothers were employed for at least 1 month during the month before conception through the third month of pregnancy.Results: The prevalence of estimated occupational PAH exposure was 9.0% in case mothers (27 of 299) and 3.6% in control mothers (107 of 2,993). Logistic regression analyses indicated a significant association between occupational PAHs and gastroschisis among mothers ≥ 20 years of age [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.27, 5.04] after adjusting for maternal body mass index, education, gestational diabetes, and smoking. This association was not seen in mothers < 20 years (OR = 1.14; 95% CI: 0.55, 2.33), which is notable because although young maternal age is the strongest known risk factor for gastroschisis, most cases are born to mothers ≥ 20 years.Conclusion: Our findings indicate an association between occupational exposure to PAHs among mothers who are ≥ 20 years and gastroschisis. These results contribute to a body of evidence that PAHs may be teratogenic.     

Risk of birth defects among children conceived with assisted reproductive technology: providing an epidemiologic context to the data

Studies of assisted reproductive technology (ART) and birth defects must be scrutinized and appropriately interpreted in the context of their limitations. The recent findings reported by Klemetti et al. are compelling, given the study's many strengths, and add to the accumulating evidence suggestive of an association between ART and birth defects.     

Using Supervised Learning Methods to Develop a List of Prescription Medications of Greatest Concern during Pregnancy

Maternal and Child Health Journal - Women and healthcare providers lack adequate information on medication safety during pregnancy. While resources describing fetal risk are available, information...