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Motivation: A gene regulatory network in which the modes (activation/inhibition) of the transcriptional regulations are known and in which gene expression assumes boolean values can be treated as a system of linear equations over a binary field, i.e. as a constraint satisfaction problem for an information code., Results: For currently available gene networks, we show in this article that the distortion associated with the corresponding information code is much lower than expected from null models, and that it is close to (when not lower than) the Shannon bound determined by the rate-distortion theorem. This corresponds to saying that the distribution of regulatory modes is highly atypical in the networks, and that this atypicality greatly helps in avoiding contradictory transcriptional actions. Choosing a boolean formalism to represent the gene networks, we also show how to formulate criteria for the selection of gates that maximize the compatibility with the empirical information available on the transcriptional regulatory modes. Proceeding in this way, we obtain in particular that non-canalizing gates are upper-bounded by the distortion, and hence that the boolean gene networks are more canalizing than expected from null models.

Objective: Inhibin and activin are proteins produced by ovarian granulosa cells and testicular Sertoli cells and are members of the transforming growth factor-beta superfamily. Since increased circulating levels of immunoreactive inhibin were detected in women with malignant ovarian tumors, they were proposed as tumor markers for ovarian carcinoma. Immunohistochemical studies later confirmed the presence of inhibin and activin subunits in granulosa cell tumors and epithelial ovarian cancer, as well as in Sertoli and Leydig cell testicular cancer. However, there is discrepant information on the detection of inhibin and activin in malignant germ cell tumors (MGCT). The aim of the present study was to evaluate the immunohistochemical expression of the inhibin/activin alpha, betaA and betaB subunits in ovarian and testicular MGCT specimens using polyclonal antisera., Methods: The ovarian tissue samples were composed of 19 MGCT, including dysgerminoma (n=18) and yolk sac tumor (n=1). The testis specimens included classic seminomas (n=20), embryonal carcinomas (n=7), choriocarcinomas (n=2), and yolk sac tumor (n=1)., Results: Ovarian and testicular malignant germ cell tumors expressed positive staining for inhibin/activin alpha, betaA and betaB subunits, with some variations between and within individual tumors: while ovarian dysgerminomas were diffusely positive for alpha, betaA and betaB, testicular tumors expressed alpha and betaB subunits, whereas betaA staining was weak., Conclusions: The present results show positive staining for inhibin/activin subunits in ovarian and testicular MGCT, suggesting a possible role in tumorigenesis with the resultant clinical implication.

Background: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in preclinical studies. We determined the efficacy of fenretinide in preventing a second breast malignancy in women with breast cancer., Methods: We randomly assigned 2972 women, aged 30-70 years, with surgically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The primary end point was the incidence of contralateral breast cancer or ipsilateral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence were determined by Cox proportional hazards regression analysis. Statistical tests were two-sided., Results: At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P =.642) or ipsilateral breast cancer (P =.177) between the two arms. However, an interaction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes =.045), with a possible beneficial effect in premenopausal women (contralateral breast cancer: adjusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1.07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0. 92) and an opposite effect in postmenopausal women (contralateral breast cancer: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: adjusted HR = 1.19, and 95% CI = 0.75-1. 89). There were no statistically significant differences between the two arms in tumors in other organs, incidence of distant metastasis, and all-cause mortality., Conclusions: Fenretinide treatment of women with breast cancer for 5 years appears to have no statistically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered exploratory and need to be confirmed.

Background: Genital infection with certain strains of human papillomavirus (HPV) is associated with a high risk of malignant transformation, and HPV-associated cervical intraepithelial neoplasia (CIN) can become invasive cancer. Host factors are critical in regulating tumor growth, and cytokines that modulate immunologic control may be of particular importance. The type 1 cytokines interleukin 2 (IL-2) and interferon gamma (IFN gamma) are immunostimulatory and are thus capable of limiting tumor growth. The type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10) are immunoinhibitory and are thus capable of stimulating tumor growth., Purpose: We analyzed the production of cytokines by peripheral blood mononuclear cells (PBMCs) in women with CIN associated with localized or extensively spread HPV infection., Methods: Thirty women diagnosed with CIN and 10 age- and sex-matched healthy control subjects were enrolled in the study conducted at Istituto Nazionale Tumori, Milan, Italy. The following parameters were analyzed: 1) HPV infection of the cervix and other sites of the lower genital tract by colposcopic, cytologic, and histologic examinations; 2) HPV typing; 3) in vitro production of IL-2 by PBMCs in response to stimulation with soluble antigen (influenza [FLU] antigen) or to cell-associated human leukocyte antigen (HLA) alloantigen; and 4) in vitro production of the type 1 cytokines IL-2 and IFN gamma and of the type 2 cytokines IL-4 and IL-10 by PBMCs in response to mitogen stimulation. Statistical significance was determined by nonparametric tests (two-sided)., Results: High-grade CIN associated with HPV infection was detected in all case patients, and HPV type 16 or 18 infection was detected in cervical tissue of 21 (70%) of 30 case patients. HPV infection that had spread to other sites of the lower genital tract, thus resulting in more extensive disease, was detected in 16 (53%) of the 30 individuals with CIN, whereas HPV infection was limited to the portio in 14 (47%). IL-2 production by PBMCs in response to stimulation with soluble antigen or HLA alloantigen was reduced in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. In contrast, IL-4 and IL-10 production in response to mitogen stimulation was elevated in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. The highest production of IL-4 and IL-10 was detected in patients with HPV infection that had extended beyond the genital tract., Conclusions: CIN is characterized by different immunologic profiles, in which HPV infection is or is not confined to the portio. Production of cytokines that mainly enhance potentially protective cell-mediated immunity is defective in the women in whom extended HPV infection was observed. A pronounced shift from type 1 to type 2 cytokine production is associated with more extensive HPV infection., Implications: These data reinforce the need for detailed analyses of immune dysregulation in CIN patients. They also suggest the potential usefulness of the cytokine assays for determining prognosis or deciding whether cytokine-based therapy is indicated.

Fenretinide [N-(4-hydroxyphenyl)retinamide, 4-HPR] is an effective agent for the inhibition of N-nitroso-N-methylurea-induced breast cancer in rats. This compound has been studied extensively and proved to be safer and less teratogenic than many other retinoids. A major characteristic of 4-HPR is its ability to concentrate in the granular and fat tissue of the breast instead of in the liver. Between January and June 1986, we carried out a phase I study on 101 patients divided into four randomized groups receiving placebo and 100, 200, and 300 mg/day of 4-HPR. Patients received the drug for 6 months without any major toxic effect. This finding was confirmed by another 6-month study in which patients received a common dose of 200 mg/day. In March 1987, a phase III study was started to evaluate the effectiveness of 4-HPR in preventing contralateral primary tumors in women who had already been treated for breast cancer. If 4-HPR succeeds in preventing second primaries in breast cancer patients, it may be useful for a wider group of subjects at high risk for breast cancer. This randomized study was designed with two arms: an intervention group versus a group receiving no treatment. Patients in the intervention group will be treated with 200 mg/day 4-HPR for 5 years. Patients in the control group will not be treated. A further 2 years of follow-up is planned for both groups. Currently, 2450 patients have been recruited. We expect a total accrual of 3500 patients by the end of 1992.