Effect of glucocorticoids on fetoprotein production by an established cell line from Morris hepatoma 8994

Glucocorticoids at concentrations equal to or higher than 10^?7M lead to an increase of alpha-fetoprotein production by an established cell line from Morris hepatoma 8994. These cells also secreted alpha_M-fetoprotein into the culture medium but only after addition of at least 4×10^?7M hydrocortisone or 5×10^?8M dexamethasone. The effects on both fetoproteins were observed in spite of a decrease of cell multiplication and an increase of cell detachment.     

Immune competence in breast cancer — Relationship of pretreatment immunologic tests to diagnosis and tumor stage

Summary The immune competence of a group of 276 patients with suspected breast cancer has been assessed using a spectrum of tests: the peripheral lymphocyte count, serum immunoglobulin levels, lymphocyte response to phytohemagglutinin (PHA), Mantoux test, and dinitrochlorobenzene (DNCB) skin test. All tests were completed prior to any form of treatment as the initial part of an ongoing, long-term assessment which will ultimately relate immune competence to prognosis. 225 patients with breast cancer were allocated into stages based on their TNM status. The remaining 51 patients proved to have benign breast disease and made up the control group. In analysis, control patients were compared with early breast cancer patients, while the effect of advancing disease was assessed by betweenstage comparisons in the cancer group.There were no significant differences between early breast cancer and control patients or between cancer stages in peripheral lymphocyte count, serum immunoglobulin levels, lymphocyte response to PHA, or Mantoux responses. Age was found to have a crucial effect on some of these parameters and some apparent differences between the various groups lost significance after appropriate allowances were made for age.Important differences seen with the DNCB test persisted after allowing for age effects. Responses to DNCB were significantly depressed in patients with early breast cancer compared to controls. Patients with disseminated cancer showed greater depression than early breast cancer patients, but surprisingly, patients with locally advanced tumors had good responses to DNCB. Possible reasons for the paradoxical preservation of DNCB reactivity in patients with locally advanced cancer are discussed.The DNCB test is the most discriminating of the five tests of immune function studied.     

Role of pelvimetry in active management of labour.

All cases referred for pelvimetry in 1970-1 and all breech presentations referred for pelvimetry in 1972-4 were reviewed. Indications for pelvimetry fell into four main categories: high head in the antenatal clinic (47-8%); high head in labour (13-9%); breech presentation (20-9%); and previous caesarean section (14-8%). In the first two categories pelvimetry rarely if ever influenced management, and it should not be performed routinely. In breech presentation and cases of caesarean section pelvimetry seemed to be of value, but in the latter group it should be performed puerperally to avoid the known radiation hazard to the fetus. A fairly close correlation between obstetric conjugate and pelvic capacity was shown, which suggested that a 3400-g baby might pass through a pelvis of obstetric conjugate of 10 cm as a cephalic trial of labour, but would need an obstetric conjugate of 11-7 cm for safe vaginal breech delivery.     

Division of labor within the DNA damage tolerance system reveals non-epistatic and clinically actionable targets for precision cancer medicine

Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.     

The mushroom ribosome-inactivating protein lyophyllin exerts deleterious effects on mouse embryonic development in vitro

Earlier investigations disclose that some plant ribosome-inactivating proteins (RIPs) adversely affect mouse embryonic development. In the present study, a mushroom RIP, namely lyophyllin from Lyophyllum shimeji, was isolated, partially sequenced, and its translation inhibitory activity determined. Its teratogenicity was studied by using a technique entailing microinjection and postimplantation whole-embryo culture. It was found that embryonic abnormalities during the period of organogenesis from E8.5 to E9.5 were induced by lyophyllin at a concentration as low as 50 μg/ml, and when the lyophyllin concentration was raised, the number of abnormal embryos increased, the final somite number decreased, and the abnormalities increased in severity. The affected embryonic structures included the cranial neural tube, forelimb buds, branchial arches, and body axis, while optic and otic placodes were more resistant. Lyophyllin at a concentration higher than 500 μg/ml also induced forebrain blisters within the cranial mesenchyme. When the abnormal embryos were examined histologically, an increase of cell death was found to be associated with abnormal structures, indicating that cell death may be one of the underlying causes of teratogenicity of the mushroom RIP. This constitutes the first report on the teratogenicity of a mushroom RIP.     

Macromolecular adducts of ethylene oxide: a literature review and a time-course study on the formation of 7-(2-hydroxyethyl) guanine following exposures of rats by inhalation

The results of efforts to identify and quantify macromolecular adducts of ethylene oxide (ETO), to determine the source and significance of background levels of these adducts, and to generate molecular dosimetry data on these adducts are reviewed. A time-course study was conducted to investigate the formation and persistence of 7-(2-hydroxyethyl)guanine (7-HEG; Fig. 1) in various tissues of rats exposed to ETO by inhalation, providing information necessary for designing investigations on the molecular dosimetry of adducts of ETO. Male F344 rats were exposed 6 h/day for up to 4 weeks (5 days/wk) to 300 ppm ETO by inhalation. Another set of rats was exposed for 4 weeks to 300 ppm ETO, and then killed 1–10 days after cessation of exposures. DNA samples from control and treated rats were analyzed for 7-HEG using neutral thermal hydrolysis, HPLC separation, and fluorescence detection. The adduct was detectable in all tissues of treated rats following 1 day of ETO exposure and increased approximately linearly for 3–5 days before the rate of increase began to level off. Concentrations of 7-HEG were greatest in brain, but the extent of formation was similar in all tissues studied. The adduct disappeared slowly from DNA, with an apparent half-life approx. 7 days. The shape of the formation curve and the in vivo half-life indicate that 7-HEG will approach steady-state concentrations in rat DNA by 28 days of ETO exposure. The similarity in 7-HEG formation in target and nontarget tissues indicates that the tissue specificity for tumor induction is due to factors in addition to DNA-adduct formation.