Tumor Suppressor Activity of ODC Antizyme in MEK-driven Skin Tumorigenesis

To test the hypothesis that suppression of ornithine decarboxylase (ODC) activity blocks the promotion of target cells in the outer root sheath of the hair follicle initiated by Raf/MEK/ERK activation, we crossed mice overexpressing an activated MEK mutant in the skin (K14-MEK mice) with two transgenic lines overexpressing antizyme (AZ), which binds to ODC and targets it for degradation. K14-MEK mice develop spontaneous skin tumors without initiation or promotion. These mice on the ICR background were crossed with K5-AZ and K6-AZ mice on both the carcinogenesis-resistant C57BL/6 background and the sensitive DBA/2 background. Expression of AZ driven by either the K5 or K6 promoter along with K14-MEK dramatically delayed tumor incidence and reduced tumor multiplicity on both backgrounds compared with littermates expressing the MEK transgene alone. The effect was most remarkable in the MEK/K6-AZ mice from the ICR/D2 F1 cross, where double transgenic mice averaged less than one tumor per mouse for more than 8 weeks, while K14-MEK mice averaged over 13 tumors per mouse at this age. Putrescine was decreased in MEK/AZ tumors, while spermidine and spermine levels were unaffected, suggesting that the primary role played by AZ in this system is to inhibit putrescine accumulation. MEK/AZ tumors did not show evidence of apoptosis, but there was a 15–20% decrease in S-phase cells and a 40–60% decrease in mitotic cells in MEK/AZ tumors. These results indicate that the principal effect of AZ may be to slow cell growth primarily by increasing G2/M transit time

Ornithine Decarboxylase mRNA is Stabilized in an mTORC1-dependent Manner in Ras-transformed Cells

Upon Ras activation, ODC (ornithine decarboxylase) is markedly induced, and numerous studies suggest that ODC expression is controlled by Ras effector pathways. ODC is therefore a potential target in the treatment and prevention of Ras-driven tumours. In the present study we compared ODC mRNA translation profiles and stability in normal and Ras12V-transformed RIE-1 (rat intestinal epithelial) cells. While translation initiation of ODC increased modestly in Ras12V cells, ODC mRNA was stabilized 8-fold. Treatment with the specific mTORC1 [mTOR (mammalian target of rapamycin) complex 1] inhibitor rapamycin or siRNA (small interfering RNA) knockdown of mTOR destabilized the ODC mRNA, but rapamycin had only a minor effect on ODC translation initiation. Inhibition of mTORC1 also reduced the association of the mRNA-binding protein HuR with the ODC transcript. We have shown previously that HuR binding to the ODC 3′UTR (untranslated region) results in significant stabilization of the ODC mRNA, which contains several AU-rich regions within its 3′UTR that may act as regulatory sequences. Analysis of ODC 3′UTR deletion constructs suggests that cis-acting elements between base 1969 and base 2141 of the ODC mRNA act to stabilize the ODC transcript. These experiments thus define a novel mechanism of ODC synthesis control. Regulation of ODC mRNA decay could be an important means of limiting polyamine accumulation and subsequent tumour development

Pleuro-pulmonary tumours detected by clinical and chest X-ray analyses in rats transplanted with mesothelioma cells

New strategies for cancer therapy must be developed, especially in severe neoplasms such as malignant pleural mesothelioma. Animal models of cancer, as close as possible to the human situation, are needed to investigate novel therapeutical approaches. Orthotopic transplantation of cancer cells is then relevant and efforts should be made to follow up tumour evolution in animals. In the present study, we developed a method for the orthotopic growth of mesothelioma cells in the pleural cavity of Fischer 344 and nude rats, along with a procedure for clinical survey. Two mesothelioma cell lines, of rat and human origin, were inoculated by transthoracic puncture. Body weight determination and chest X-ray analyses permitted the follow-up of tumour evolution by identifying different stages. Autopsies showed that tumours localized on the whole pleural cavity (diaphragm, parietal pleura), mediastinum and pericardium. Tumour morphology and antigenic characteristics were consistent with those of the inoculated cells and were similar in both types of rats inoculated with the same cell type. These results demonstrate that mesothelioma formation in rats can be followed up by clinical and radiographic survey after gentle intrathoracic inoculation of mesothelioma cells, thus allowing the definition of stages of interest for further experimental trials. © 1999 Cancer Research Campaig

De bescherming van de burgerbevolking in gewapend conflict: over gebaande paden en nieuwe wegen

Criminal Justice: Legitimacy, accountability, and effectivit

The protection of civilians in armed conflicts: well-trodden paths and new ways forward

Criminal Justice: Legitimacy, accountability, and effectivit

The US influence in shaping Iraq's sectarian media

After the Anglo-American invasion, the US neo-conservative administration established the Iraqi Governing Council in July 2003, which included 25 members selected for their ethnic and religious origins; it was the most obvious sign of the US political separatist strategy. As a result of the new political reality, the Iraqi media was divided into ethno-sectarian lines, resulting from previous policies followed by the US administration. This article argues that the US media policy prior and after the US invasion of Iraq played a part in enhancing and encouraging the sectarian divisions in the Iraqi society. This was mainly done by sending biased media messages through the state-run Iraqi Media Network (IMN) and other US-aligned channels and allowing militant voices from different Iraqi sides to wage wars of words without interfering. In fact, the only time US officials interfered is when they were criticized by Iraqi media outlets. This study cites different US government reports, accounts from media practitioners who worked for IMN and other journalists that monitored the Iraqi media

How baseline, new-onset, and persistent depressive symptoms are associated with cardiovascular and non-cardiovascular mortality in incident patients on chronic dialysis

AbstractObjectiveDepressive symptoms are associated with mortality among patients on chronic dialysis therapy. It is currently unknown how different courses of depressive symptoms are associated with both cardiovascular and non-cardiovascular mortality.MethodsIn a Dutch prospective nation-wide cohort study among incident patients on chronic dialysis, 1077 patients completed the Mental Health Inventory, both at 3 and 12months after starting dialysis. Cox regression models were used to calculate crude and adjusted hazard ratios (HRs) for mortality for patients with depressive symptoms at 3months only (baseline only), at 12months only (new-onset), and both at 3 and 12months (persistent), using patients without depressive symptoms at 3 and 12months as reference group.ResultsDepressive symptoms at baseline only seemed to be a strong marker for non-cardiovascular mortality (HRadj 1.91, 95% CI 1.26–2.90), whereas cardiovascular mortality was only moderately increased (HRadj 1.41, 95% CI 0.85–2.33). In contrast, new-onset depressive symptoms were moderately associated with both cardiovascular (HRadj 1.66, 95% CI 1.06–2.58) and non-cardiovascular mortality (HRadj 1.46, 95% CI 0.97–2.20). Among patients with persistent depressive symptoms, a poor survival was observed due to both cardiovascular (HRadj 2.14, 95% CI 1.42–3.24) and non-cardiovascular related mortality (HRadj 1.76, 95% CI 1.20–2.59).ConclusionThis study showed that different courses of depressive symptoms were associated with a poor survival after the start of dialysis. In particular, temporary depressive symptoms at the start of dialysis may be a strong marker for non-cardiovascular mortality, whereas persistent depressive symptoms were associated with both cardiovascular and non-cardiovascular mortality

Discovery of New Molecular Subtypes in Oesophageal Adenocarcinoma

A large number of patients suffering from oesophageal adenocarcinomas do not respond to conventional chemotherapy; therefore, it is necessary to identify new predictive biomarkers and patient signatures to improve patient outcomes and therapy selections. We analysed 87 formalin-fixed and paraffin-embedded (FFPE) oesophageal adenocarcinoma tissue samples with a reverse phase protein array (RPPA) to examine the expression of 17 cancer-related signalling molecules. Protein expression levels were analysed by unsupervised hierarchical clustering and correlated with clinicopathological parameters and overall patient survival. Proteomic analyses revealed a new, very promising molecular subtype of oesophageal adenocarcinoma patients characterised by low levels of the HSP27 family proteins and high expression of those of the HER family with positive lymph nodes, distant metastases and short overall survival. After confirmation in other independent studies, our results could be the foundation for the development of a Her2-targeted treatment option for this new patient subgroup of oesophageal adenocarcinoma