The lack of Raf-1 kinase feedback regulation enhances antiapoptosis in cancer cells.

Raf-1 has an important role in cellular antiapoptosis. So far, there is no solid evidence that shows that Raf-1 mutation is associated with cancer development. In the course of further study of Raf-1 signaling, we have reported that Raf-1 hyperphosphorylation inhibits its kinase activity toward its downstream mitogen-activated protein kinase kinase 1/2 (MEK1/2) and proposed a model for negative feedback regulation of Raf-1. Here, we show that there is no hyperphosphorylation in some cancer cells, which results in increased kinase activity and enhances the antiapoptotic ability. Inhibition of either Raf-1 or ALG-2 (apoptosis-linked gene 2) expression results in apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase (ASK1/JNK) signaling activation, and cell sensitivity to chemotherapeutic reagents, indicating that inhibition of ASK1/JNK apoptotic signaling by Raf-1 is mediated by ALG-2. A previous report indicated that extracellular signal-regulated kinase 1/2 (ERK1/2) were responsible for Raf-1 hyperphosphorylation. However, our evidence shows that when ERK1/2 are activated and the Raf-1 gene is not mutated, Raf-1 is not hyperphosphorylated in these cells, indicating that ERK1/2 are not responsible for the Raf-1 hyperphosphorylation in these cancer cell lines. Surprisingly, we also found that Raf-1 is not a necessary kinase for MEK1/2 activation under normal tissue culture conditions, but is required for MEK1/2 activation under apoptosis-inducing conditions. Our research demonstrates that although Raf-1 gene is not mutated, an abnormality of Raf-1 kinase feedback regulation enhances its antiapoptotic function, and Raf-1 can still be a pharmaceutical target to increase chemotherapy or radiotherapy sensitivity in these cancer cells.

Immune Function Alterations during 12 Weeks of Abstinence in Heroin Users.

The intent of the study was to evaluate immune system changes during 12 weeks of abstinence in heroin users. We recruited men (N = 65) aged 18-45 years and collected demographic and heroin use pattern data. Serum blood levels of total interleukin 2 (IL-2), interferon γ (IFN-γ), immunoglobulin (Ig) A, IgG, and IgM were assessed at five time points. The IL-2 level was increased on day 84 as compared to that in healthy controls. The IFN-γ level was higher in heroin users than in healthy controls between days 0 and 28, and was decreased on day 84. IgG and IgM levels in heroin users were higher than those in healthy controls in our 12-week study, and were in positive correlation with the way of using the drug, duration of heroin dependence, and daily heroin intake. Our data revealed that the immune system was not restored during the 12 weeks of heroin withdrawal.

[Surgical treatment of cervical cancer].

The clinical data and long-term following up results of 1,320 cases of cervical cancer from Jan. 1 st, 1953 to Dec. 31 th 1988 were presented. The routine operative extent for invasive cervical cancer in this hospital has been radical hysterectomy and pelvic lymphadenectomy. The cardinal ligament, para-vaginal tissue and vaginal wall removed varied according to the different clinical stage and extent of the lesion. The operative complications were: trauma 0.8%, the postoperative complication of ureteral fistula 0.2%, and there were no operative death. Long-term following up rate were 99.8%. In this series. The cumulative survival rate calculated by computerized life table method were following: 5 year survival rate sq. cell ca. stage Ia 100%, stage > or = I b 97.6%; adenoma. 90.8%. 185 cases died, among which 60 cases died of recurrent cervical cancer, 85 cases died of other benign diseases, 40 cases died of primary cancers of other organs other than cervix of uteri. It denotes that once a patient suffers from one kind of cancer, she will have possibility of suffering from another kind of cancer.