We used the updated nation-wide Swedish Family-Cancer Database to examine familial risks in data from 1961 to 1998 on 1252 invasive and 2474 in situ squamous cell carcinoma (SCC) of the skin among offspring, and over 10 times more among parents. In 259 families a parent and an offspring had skin SCC. The familial standardised incidence ratios (SIRs) were 2.72 for invasive and 2.40 for in situ skin cancers in offspring. Multiple skin cancers in parents were associated with increased SIRs for invasive SCC in offspring, being 2.55 for one and up to 14.93 for two invasive and two in situ cancers in parents; the corresponding in situ SCC risks were 2.28 and 7.49. The population attributable fraction for any familial skin SCC, invasive or in situ, was 4.1%. Melanoma was the only discordant tumour that was associated with invasive and in situ skin SCC. These results provide evidence that there is an underlying hereditary susceptibility for at least a part of the familial clustering for skin SCC. Squamous cell carcinoma (SCC) of the skin is not recorded by most cancer registries and its established risk factors are limited to fair skin, ultraviolet light, arsenic compounds and immunosuppression, while less is known about benign lesions, such as actinic keratosis and in situ carcinoma (intraepidermal SCC, or Bowen's disease) (IARC, 1990(IARC, , 1995English et al, 1997) The Swedish Cancer Registry has recorded both invasive and in situ SCC whose incidence has rapidly increased over the past 20 years (Center for Epidemiology, 2000;Wassberg et al, 2001). Skin SCC is the fourth most common cancer in men and women in Sweden in 1998, and the in situ form is the most common benign/precancerous tumour in men and the second among women after in situ cervical cancer. In situ skin cancer does not appear to be a simple precursor lesion to invasive SCC because the age of onset of the two forms is similar; a true precursor lesion would be expected to show an earlier age of onset, as with cervical in situ and invasive cancers
SummaryTwo mutants of human immunodeficiency virus (HIV) reverse transcriptase (RT), Tyr181 to Cys and Leu100 to lie, have been prepared and characterized by use of various inhibitors. As compared to~~type RT the mutant RT's had lower KeatlK m values. The K m values were lower with heteropolymeric than with homopoIymeric template-primers. Inhibition by phosphonoformate was of mixed type with both wild-type and mutant RT's and the mutants were less sensitive to phosphonoformate than the wild type RT. The nonnucleoside RT inhibitors 9-CI-TIBO and L-697,661 gave a non-competitive inhibition with respect to substrate of the wild type RT. The mutant RT's were inhibited at higher concentrations, showing a mixed type of inhibition with respect to substrate. ddGTP caused a competitive inhibition of wild type and mutant RT's with respect to substrate, RT preparations with different mutations are useful in rapidly characterizing the interaction between various inhibitors and HIV RT and thus facilitate the development of new inhibitors.
SummaryTrovirdine (LY300046·HCI) is a potent and selective non-nucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor (Ahgren et al., Antimicrob Ag Chemother 39: 1329. Combinations of trovirdine with other RT inhibitors, AZT, ddC, ddl and their triphosphates, were studied as well as the pyrophosphate analogue PFA in both cell-free HIV-1 polymerase assays and HIV-1-infected MT-4 cell cultures. Synergistic effects and weak synergism were observed both using RT and HIV-1-infected cells and using different HIV-1 RT mutants and HIV-1 drug-resistant variants known to be resistant to the inhibitory effects of trovirdine. The best combination with substantial synergism was ddC-TP and trovirdine at a 20:1 molar ratio combination in a cell-free enzyme assay. This combination showed the weak synergy in MT-4 cells. Synergism was judged by the median-effect method. The inhibitory effect of trovirdine was independent of increased concentrations of AZT triphosphate and ddC triphosphate implying that trovirdine acts in a mutually exclusive manner with AZT-TP and ddC-TP as determined by the Dixon plot. The combination effects were expressed by the combination index (CI) using end points of 50%, 70% and 90% inhibition of HIV-1 RT activity and HIV-1 replication in MT-4 cells.
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