Von Hippel-Lindau-coupled and transcription-coupled nucleotide excision repair-dependent degradation of RNA polymerase II in response to trabectedin

PURPOSE: Ecteinascidin 743 (Et743; trabectedin, Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II. Experimental Design and RESULTS: We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation. We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency. CONCLUSION: These results suggest that both TC-NER-induced and VHL-mediated Pol II degradation play a role in cell killing by Et743.     

Communicating with women about mammography

Background/Methods. We report survey results of the types of tools used to communicate with women about breast cancer screening and the content areas included in each tool for member countries of the International Breast Cancer Screening Network (IBSN).Results. In addition to using pamphlets and invitation letters, new technologies are being used such as the Internet which allows for easy updating of information and can provide interactive modules. Several countries have addressed the needs of specific populations such as indigenous populations or blind women. All countries provide basic information, although they do not provide all the same information.Conclusion. More research is needed to understand what women need to make an informed decision about mammography and to learn what the best modalities are to provide this information.     

Cleavage of tensin during cytoskeleton disruption in YTX-induced apoptosis.

Yessotoxin (YTX) is a marine algal toxin previously shown to induce apoptosis in L6 and BC3H1 myoblast cell lines. Disassembly of the F-actin cytoskeleton and cleavage of tensin, a cytoskeletal protein localised at the focal adhesion contacts, appear during this apoptotic process. Tensin binds to actin filaments at the focal adhesion contacts and it links the actin cytoskeleton to the extracellular matrix (ECM). This binding occurs via integrin receptors and it makes tensin a potential link between the actin cytoskeleton and signal transduction. This study evaluates disruption in the F-actin cytoskeleton and change of tensin in myoblast cell lines exposed to 100 nM YTX up to 72 h. YTX treatment cleaves tensin and makes it translocate to the cell centre. Tensin has normally a role in the maintenance of cell shape and YTX-treatment may therefore alter the shape of the cells. YTX exposure also induces formation of lamellas associated with pseudopodia. Alternative linkages and cytoskeletal proteins anchoring the actin filaments to focal contacts remain to be identified.     

Exposure to dioxin-like pollutants via different food commodities in Swedish children and young adults

The dietary intake of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) in terms of toxic equivalents (TEQs) was investigated in Swedish children and young adults. Exposure was estimated from concentration data of six groups of individual food commodities (meat, fish, dairy products, egg, edible fats and other foodstuff) combined with food intake data from a 7-day record book obtained from 670 individuals aged 1–24 years. The results showed that Swedish boys and girls, up to the age of ten, had a median TEQ intake that exceeded the tolerable daily intake (TDI) of 2 pg TEQ/kg body weight. Children exceeding the TDI varied from almost all individuals among the youngest children to about 20% among young men and women. Dairy and fish products were the main sources of exposure for the average child, accounting for 59% of the total TEQ intake. The individuals most highly exposed were, on the other hand, characterized by a high consumption of fish. Since children constitute a vulnerable group, results obtained from the present study show that it is essential to perform age specific dietary intake assessments of pollutants and more carefully consider sensitive and/or highly exposed groups in the population in the risk management processes.     

Completeness and accuracy of registration of ovarian cancer in the cancer registry of Norway

Completeness of reporting and accuracy of the diagnosis of ovarian cancer from one health region in Norway to the Cancer Registry were examined. Data kept by the Cancer Registry were evaluated against discharge diagnosis data from all 8 hospitals in the health region during the period of 1987-1996. The assessment of the accuracy of the diagnosis recorded in the Cancer Registry was based on review of all medical records in the hospital setting and on slide review of all histologic diagnoses. The overall completeness of reporting ovarian cancer to the Cancer Registry was 99.6%. The organ specific completeness of registration of histologic verified ovarian cancer within the Cancer Registry was 95.3%; 0.9% was erroneously coded and 3.5% had their diagnosis changed to ovarian cancer at re-evaluation. Of all ovarian cancer cases registered at the Cancer Registry, 91% had a primary histologic diagnosis. Among 591 cases identified with a histologic diagnosis in the Cancer Registry, the accuracy of the diagnosis was estimated at 92%. Coding errors were found in 2% of these cases, while in 6% of the cases it was not possible to reproduce the original diagnosis of ovarian cancer at re-evaluation. In order to provide data of high quality for cancer surveillance a cancer registry needs several data providers, such as histopathologic laboratory reports and clinical reports. In addition, assessment of reported data through stringent quality assurance procedures within the registry are necessary for reaching a nearly 100% completeness of registration as found for ovarian cancer in the Cancer Registry of Norway.     

Triplet Placentas: Reference Values for Weights

The occurrence of twins, triplets, and other multiple births increased significantly between 1970 and 2000 in the United States and other industrialized countries. The number of triplet placentas submitted for examination as pathologic specimens has also markedly increased, but no reference values are published for triplet weights. We examined 196 normal triplet placentas. Specimens with associated conditions known to affect the weights of the placentas were excluded. The gestational ages ranged between 20 and 38 weeks. Mean weights for different gestational ages are summarized as follows: 253 g for 20 weeks, 319 g for 22 weeks, 406 g for 24 weeks, 509 g for 26 weeks, 621 g for 28 weeks, 738 g for 30 weeks, 855 g for 32 weeks, 965 g for 34 weeks, 1065 g for 36 weeks, and 1147 g for 38 weeks. Weight gain of triplet placentas appears to parallel that of twin placentas. The mean values of placental weights for triplets at each gestational age are less than triple those of singleton weights for the same duration of gestation. The placental weights in multiple gestations do not increase proportionately with the number of fetuses.     

Late onset postpartum thrombocytosis in preeclampsia

BACKGROUND: During pregnancy, changes in blood coagulation and fibrinolysis create a hypercoagulable state. In the puerperium this thrombogenicity is even higher, and the chance of developing thromboembolism is 3-5 times higher in this period than during pregnancy. In preeclampsia, platelets are activated and play a substantial role in the pathogenesis of the disease. Systematic information on longitudinal changes in platelet number and size postpartum after normotensive and preeclamptic pregnancies is not available. METHODS: We measured platelet number, mean platelet volume and the median volume of the 20% largest platelets in eleven preeclamptic and eleven normotensive pregnant women matched for mode of delivery. The blood samples were taken antepartum and every 2-3 days in the postpartum period until the platelet count decreased/normalized. RESULTS: In the preeclamptic group, the platelet count increased significantly from 240x10(9)/l antepartum to 621x10(9)/l on day 6-14 postpartum (p<0.01). In the control group, the platelet count increased from 214x10(9)/l antepartum to 251x10(9)/l on day 2-5 (p<0.01) and 351x10(9)/l on day 6-14 postpartum (p<0.01). The platelet count was significantly higher in the preeclamptic than in the control group 6-14 days postpartum (p<0.01). Antepartum, mean platelet volume and the median of the 20% largest platelets were significantly higher in the preeclamptic than in the control group. CONCLUSION: The platelet count is significantly increased postpartum both after normotensive, and 2-3 fold more after preeclamptic pregnancies. The time to peak values is between 6-14 days, usually at a time when patients are discharged from hospital.     

Single-strand breaks in DNA of various organs of mice induced by styrene and styrene oxide

Styrene and its metabolite styrene oxide were given i.p. to mice. The induction of single-strand breaks (SSB) in DNA was studied with the DNA unwinding technique. The level of SSB in kidney-DNA was a linear function of the dose for both substances. Styrene and styrene oxide induced an increase in the level of SSB in DNA of kidney, liver, lung, testis and brain 1 h after administration. After 24 h the damage remained on an enhanced level in liver, lung and testis after styrene oxide administration and in all organs except liver after styrene administration.