Disc large 1 expression is altered by human papillomavirus E6/E7 proteins in organotypic cultures of human keratinocytes.

Loss of cell polarity is a fundamental process in cell transformation. Among polarity proteins, we focused on human disc large (DLG1), which is localized mainly at adherens junctions and contributes to the control of cell proliferation. We previously demonstrated that its expression is altered in HPV-associated cervical neoplastic lesions, but the mechanisms beyond this remain unknown. In this study, we analysed the contribution of HPV proteins to the changes in DLG1 expression in the squamous epithelium. We observed tissue and intracellular misdistribution of DLG1 when high-risk HPV-18 E7 or E6/E7 proteins were expressed in organotypic raft cultures. The viral oncoproteins induce the loss of DLG1 from the cell borders and an increase in the level of DLG1 protein, reflecting the pattern observed in cervical lesions. These findings were corroborated in cultures bearing the entire HPV-18 genome. Interestingly, changes in tissue distribution and abundance of DLG1 were also detected in organotypic cultures expressing the low-risk HPV-11 E7 or E6/E7 proteins, suggesting a conserved function among different HPV types. However, for low-risk HPVs, the subcellular localization of DLG1 at cell-to-cell contacts was predominantly maintained. This report offers new evidence, we believe, of the involvement of HPV proteins in DLG1 expression pattern and our data support previous observations regarding DLG1 expression in cervical lesions.

HPV-mediated genome instability: at the roots of cervical carcinogenesis.

Human papillomaviruses are small DNA viruses that cause hyperproliferative lesions of the mucosa and skin. Some HPV types, collectively known as high-risk types, are etiologically associated to cervical cancer and other anogenital malignancies. Infection by these HPV types has been associated to genomic instability, a hallmark of most human malignancies. High-risk HPV types express two oncoproteins, E6 and E7, which target specific cellular factors to promote cell proliferation. Furthermore, these proteins induce structural and numerical chromosome alterations and modulate cellular response to DNA damage. These observations are discussed in the context of cervical carcinogenesis.

Viral origins of human cancer.

The first consistent observations that viruses could be associated with some types of cancer where made almost a century ago. Since then researchers have spent a great deal of effort to address the infectious origins of human cancer. As a result of these studies, a strong link between some viral agents and several human cancers has been established. Some viruses as the Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell lymphotropic virus type I (HTLV-I), immunodeficiency virus type I (HIV-I) and several human papillomavirus types (including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66) have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC). Infection by these viruses constitutes a heavy burden for human populations as it accounts for almost 15% of all human malignancies. Furthermore, many other viral agents have been classified as possibly carcinogenic to humans and others have been occasionally found in human tumors suggesting that this figure may be an underestimation of virus involvement in the etiology of human cancer. Therefore, viral infection appears as one of the main preventable cancer risk factors. We summarize the current state of knowledge concerning virus-induced/associated cancers and discuss its significance in the context of human carcinogenesis. Prevention and control of infection by these agents could dramatically reduce the incidence of some prevalent cancers and, consequently, have a great impact on public health.

Hepatitis C: a critical analysis of therapeutic response predictors.

Treatment of chronic hepatitis C is still unspecific. However, there is great expectancy concerning the new pegylated interferons. As there has been much controversy about the best parameters to determine whether treatment is effective, we analyzed several criteria currently used for evaluation, including serum alanine aminotransferase (ALT) normalization, viral load reduction and improvement of hepatic histology.

Hepatitis C: a critical analysis of therapeutic response predictors

Treatment of chronic hepatitis C is still unspecific. However, there is great expectancy concerning the new pegylated interferons. As there has been much controversy about the best parameters to determine whether treatment is effective, we analyzed several criteria currently used for evaluation, including serum alanine aminotransferase (ALT) normalization, viral load reduction and improvement of hepatic histology.

Intrachromosomal localization of aberration breakpoints induced by neutrons and gamma rays in Chinese hamster ovary cells.

Chromosome breakpoints induced by neutrons or gamma rays in Chinese hamster ovary cells were mapped to Giemsa-light or Giemsa-dark bands or to band junctions. Radiation-induced breakpoints were found to be distributed nonrandomly according to chromosome or band length. More than 60% of the breakpoints were localized in G-light bands. A group of 13 bands which corresponded to only 7% of the total chromosome length contained 22% of the breakpoints produced by neutrons and 14% of those induced by gamma rays. Seven of these 13 bands are also preferentially damaged by AluI, BamHI and DNase I as reported previously. The results indicate that chromatin and nuclear structure may play a role in the distribution of breakpoints produced by ionizing radiation and endonucleases.

Localization of chromosome breakpoints: implication of the chromatin structure and nuclear architecture.

Restriction endonucleases and ionizing radiations have been extensively used to study the origin of chromosomal aberrations. Although a non-random distribution of chromosome breakpoints induced by these agents has been claimed by several authors, the significance of the chromatin structure and nuclear architecture in the localization of breakpoints is still not well understood. Breakpoint patterns produced by endonucleases targeted to specific genome sequences or by ionizing radiations could provide additional evidence to clarify this point. Results obtained from the localization of breakpoints induced by AluI, BamHI or DNase I as well as by neutrons or gamma-rays in G-banded Chinese hamster ovary (CHO) chromosomes are presented. AluI and BamHI were electroporated into CHO cells either during the G1 or S-phase of the cell cycle. A co-localization of breakpoints was found with a preferential occurrence in G-light bands independent of the cell cycle stage in which aberration production took place. Since AluI and BamHI recognition sequences are partitioned in the housekeeping and tissue-specific subgenomes respectively, we postulated that nuclease sensitive sites in active chromatin could be the main targets for the induction of breakpoints by these endonucleases. This assumption is supported by the finding that DNase I-induced breakpoint patterns in CHO cells are similar to those produced by AluI and BamHI. Digestion of fixed CHO chromosomes with these endonucleases induced G-banding suggesting a higher sensitivity of G-light chromatin. For comparison purposes, CHO cells were irradiated with neutrons or gamma-rays and breakpoints localized in G-banded chromosome aberrations. A higher occurrence of breakpoints in G-light bands was also observed. We detected seven breakage-prone G-light bands that were preferentially damaged by the three endonucleases and by both types of radiation. These results emphasize the possible implication of the chromatin structure and the nuclear architecture in the localization of chromosome breakpoints induced by endonucleases, neutrons and gamma-rays.

Antiemetic efficacy of granisetron in patients with gynecological malignancies.

The efficacy and tolerability of granisetron in the management of acute and delayed emesis was compared with that of a multiple antiemetic drug combination regimen, including metoclopramide, dexamethasone, lorazepam and orphenadrine. The trial was a randomized, cross-over study involving 111 patients with gynecological cancers undergoing chemotherapy with cisplatin. Granisetron was significantly more effective than the combination regimen during the first 24 h after chemotherapy; complete response, rates were 67 and 48%, respectively (p = 0.002). There was a significant reduction in the effectiveness of the combination during the second treatment cycle, compared with the first. In contrast, the efficacy of granisetron did not differ between the two cycles. The response rate during the 6 days after chemotherapy was 40.8% in both groups. At the end of the study, 55% of patients preferred granisetron and 23% preferred the combination (p < 0.001). Granisetron was well tolerated. The principal adverse event was headache, which was reported in 7% of patients. The results of this study confirm that granisetron is effective in the treatment of cisplatin-induced nausea and vomiting during the 24 h after chemotherapy.

Localization of chromosome breakpoints induced by DNase I in Chinese hamster ovary (CHO) cells.

DNase I was electroporated into S-phase CHO cells and induced chromosome breakpoints were localized in G-banded metaphases. More than 75% of breakpoints mapped to Giemsa-light bands, 18% to Giemsa-dark bands and about 7% to band junctions. Chromosome breakpoint clusters produced by DNase I colocalized with chromosome breakpoints induced by the restriction endonucleases AluI and BamHI in the G1- and S-phases of the cell cycle in CHO cells. Digestion of metaphase spreads with AluI, BamHI and DNase I produced G-bands, indicating that G-light bands are more sensitive to endonuclease action. The possible role of nuclease-sensitive sites in active chromatin as selective targets for the induction of chromosome breakpoints by these endonucleases is discussed.

Oral contraception and breast pathology.

After a rapid examination of the international literature concerning human, animal, histological and epidemiological experimental data, the Authors state that the use of oral contraceptives considerably reduces the risk of benign disease of the breast. This risk reduction seems to be connected to the presence of progestin in this type of contraception. The Authors then expound the data regarding a group of patients (3527), who came to the center for the diagosis and prevention of cancer of the breast at the S. Martino hospital of Genoa during the years 1977-1980. The results of the study are comparable to those found in international literature, in that they confirm the protective effect of hormonal contraception on benign pathology of the breast. Finally we have shown the data of the retrospective and prospective studies conducted up till now on the effects of hormonal contraception on malignant breast pathology. In conclusion we have shown which lines of study should be taken in order to clarify once and for all the links existing between estroprogestins and cancer of the breast.

PIP: Extensive studies conducted on laboratory animals have shown that administration of estroprogestin at the doses used in the preparation of human hormonal contraceptives do not cause any mammary alterations of either the benign or malignant type. A review of the published literature on the cytological and histological studies conducted in humans on both normal and pathological mammary tissue have been unable to show any particular microscopic aspects which distinguished users of estroprogestins from women who do not use this type of contraception, both in the case of benign and of malignant lesions. Published literature shows a reduction of about 20% of the risk of benign breast disease in women using oral contraception (OC) as compared to nonusers; this benign effect of OC use is seen in all age groups, and it seems to be linked to the presence of progestin in the contraceptives. A research study was done on a group of 2104 women aged 20-50 who had come to the breast cancer center of the San Martino Hospital in Genova, Italy, during the period 1977-80. 79.6% of women had never used contraception, 6.6% had been using estroprogestins for more than 2 years, 2.5% had been using the mini-pill for more than 2 years. Fibroadenoma was found in 22% of women who had not used OC, in 20% of those who had used it for a year or less, and in 15% of those who had used it for more than 2 years; cystic diseases were found in 29%, 25%, and 16% of the patients, respectively. The incidence of benign breast lesion was not linked with age, and was lower in women who had used the highest progestin content. Most retrospective and prospective studies have concluded that there is no epidemiological data or evidence to demonstrate that OC use is linked to the development of malignant breast tumors in women under 40 years of age. This does not exclude the possibility that one or more risk factors for the development of breast cancer (age, nulliparity, familial antecedents, viral factors, radiation, age at first pregnancy) can be modified by the use of OC. Further studies must be made in order to define more clearly the connection between OC use and breast cancer, especially in women who have been exposed to estroprogestins for prolonged periods of time.

The amenorrhoea-galactorrhea syndrome: present diagnostic and therapeutic perspectives. / La sindrome amenorrea-galatorrea: prospettive diagnostiche e terapeutiche attuali

Recent progress in the field of radioimmunology, especially as regards prolactin (PRL) assay, as well as the use of new drugs have opened new perspectives for a better understanding of the "amenorrhoea-galactorrhea syndrome" both from the diagnostic and therapeutic points of view. This syndrome which formerly was considered infrequent, is now observed more and more often, perhaps as a result of the more widespread use of drugs such as phenothiazines, reserpine derivatives, alpha-methyldopa and tricyclic antidepressants, as well as owing to the large-scale use of estrogens and above all of estrogen-progestogen contraceptives. The problems of etiopathogenesis and management of the amenorrhea-galactorrhea syndrome are complicated by the fact that a variety of factors are responsible, as is shown also by the classical nosographic classification with the Forbes-Albright syndrome in the presence of a pituitary tumour, the Chiari-Frommel syndrome of amenorrhea-galactorrhea following pregnancy, and the Argonz-del Castillo-Ahumada syndrome in the absence of lither pregnancy or tumor.