Thymidine selectively enhances growth suppressive effects of camptothecin/irinotecan in MSI+ cells and tumors containing a mutation of MRE11

PURPOSE: DNA synthesis inhibitors and damaging agents are widely used in cancer therapy; however, sensitivity of tumors to such agents is highly variable. The response of tumor cells in culture to these agents is strongly influenced by the status of DNA damage response pathways. Here, we attempt to exploit the altered response of mismatch repair (MMR)-deficient colon cancer cells and tumors to camptothecin or irinotecan and thymidine by combining them to improve therapeutic response. EXPERIMENTAL DESIGN: A panel of colon cancer cell lines was assayed for response to camptothecin-thymidine combinations by measuring colony formation, cell cycle distribution, and senescence. Cell strains defective in p53, p21, or Mre11 were used in these assays to investigate the role of these cell cycle regulators. The in vivo antitumor response of xenografts to irinotecan and thymidine combinations was assessed in nude mice. RESULTS: Camptothecin-thymidine combinations suppress colony formation of MMR-deficient tumor cells 10- to 3,000-fold relative to that obtained with camptothecin alone and significantly reduce the concentrations of the agents required to induce late S/G(2) arrest and senescence. Sensitivity is not a direct result of MMR, p53, or p21 status. However MMR-deficient cell lines containing an intronic frameshift mutation of MRE11 show greatest sensitivity to these agents. Increased sensitivity to this combination is also evident in vivo as thymidine enhances irinotecan-induced growth suppression of MMR-deficient tumors carrying the MRE11 mutation in mouse xenografts. CONCLUSION: Irinotecan-thymidine combinations may be particularly effective when targeted to MSI+ tumors containing this readily detectable MRE11 mutation.     

Toxicity and Bioaccumulation of Copper to Black Bindweed (Fallopia convolvulus) in Relation to Bioavailability and the Age of Soil Contamination

The use of ecotoxicity test results obtained in the laboratory for prediction of effects of potentially toxic concentrations of chemicals in the field is hampered by several factors differing between the laboratory and the field situations. One important factor is the binding of test chemicals to soil, which is affected by the age of the contamination and soil type. The present study investigated the effect of contamination age by introducing an aging period of 1 to 12 weeks between mixing the test substance, copper sulfate, in with soil and introducing the test plant, Fallopia convolvulus (L.) A. Löve. Copper accumulation, emergence of cotyledons, and growth were assessed and related to total (boiling with HNO₃) and 0.01 M CaCl₂- and DTPA-extractable soil copper concentrations. Aging of the copper-contaminated soil had only small effects on bioaccumulation of copper, copper toxicity, and extractable soil copper fractions. Soil copper had no effect on emergence of cotyledons. Estimated EC₅₀ values for shoot and root growth averaged 280 mg Cu/kg. Effects on growth in these laboratory-treated soils were much more severe than in a study performed in soil from an old copper-contaminated field site. Neither CaCl₂- nor DTPA-extractable copper fractions could explain all of the differences in effects between aged spiked soil and field soil. The accumulation pattern for roots and shoots of F. convolvulus indicated that excessive copper was accumulated and adsorbed mainly by the fine roots, whereby the copper concentrations of other plant parts were kept low until the plant was no longer able to maintain this regulation. An internal threshold for effects on growth of about 20 mg Cu/kg shoot dry weight was estimated, coinciding with a soil copper concentration of approximately 200 mg/kg.     

Suicidal ideation and suicide attempts among adult Danes

This study describes the prevalence of suicidal ideation and attempted suicide in a representative survey among adults in Denmark and gives the proportion of people reporting a suicide attempt that results in contact with the health care system. The data for the 1994 Danish national health interview survey were collected by personal interview and a self-administered questionnaire. A subsample of 1362 individuals participated in the part of the survey that addressed suicidal behaviour (64% of the random sample). The results show that 6.9% reported having had suicidal thoughts within the past year. Averaging across all age groups the overall prevalence of people reporting ever having made a suicide attempt was 3.4% and the one-year prevalence was 0.5%. Suicidal ideation was more prevalent among young people than among older people, whereas ever-attempted suicide showed no age gradient. Both suicidal ideation and ever-attempted suicide were more prevalent among economically inactive people (e.g. unemployed) and among unmarried or divorced people. We estimate that 50-60% of suicide attempts reported in a representative, national survey become known to the healthcare system.     

The Effect of 3'-Deoxyadenosine N1-Oxide on Growth in Vitro and in vivo on Ehrlich Ascites Tumor and on a Human Squamous Lung Cell Carcinoma Xenograft in Nude Mice

The effect of 3'-deoxyadenosine N¹-oxide (3'-dANO) on Ehrlich ascites tumor and a human squamous lung cell carcinoma was investigated. The 3'-dANO concentration that inhibited the cell growth 50% (IC₅₀) in Ehrlich ascites tumor cells in vitro was 0.15 mM, and the killing efficiency concentration (concentration of the drug that kills all cells) was 1 mM. By simultaneous administration of 3'-dANO and the adenosine deaminase inhibitor erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), the IC₅₀ of 3'-dANO was unchanged, but the killing efficiency concentration of 3'-dANO was reduced to 0.3 mM. When mice bearing Ehrlich ascites tumor were treated i.p. with 3'-dANO doses of 200 mg/kg daily for 4 days, the mean increased life span (ILS) was 200%. 3'-dANO in combination with EHNA did not further increase the life span of the tumor-bearing mice. The specific growth delay (SGD) of the Ehrlich tumor and of a human squamous lung cell carcinoma growing subcutaneously in 3'-dANO-treated mice were calculatedfrom Gomperts tumor growth curves. The Ehrlich tumor-bearing mice received 3'-dANO i.p. at doses of 250 mg/kg daily for 4 days, and the nude mice bearing human carcinoma received 3'-dANO i.p. at doses of 225 mg/kg daily for 5 days. The SGD for the investigated tumors were calculated to be 1.0 and 1.1, respectively.     

Human retinal pigment epithelial cells inhibit proliferation and IL2R expression of activated T cells

The purpose of this study was to characterize the effects of human retinal pigment epithelial (RPE) cells on activated T cells. Activated T cells were cocultured with adult and foetal human RPE cells whereafter apoptosis and proliferation were determined by flow cytometry and (3)H-Thymidine incorporation assay, respectively. T cells and RPE cells were cultured directly together or in a transwell system for determination of the effect of cell contact. The importance of cell surface molecules was examined by application of a panel of blocking antibodies (CD2, CD18, CD40, CD40L, CD54, CD58) in addition to use of TCR negative T cell lines. The expression of IL2R-alpha -beta and -gamma chains of activated T cells was analysed by flow cytometry after incubation of T cells alone or with RPE cells. Human RPE cells were found to inhibit the proliferation of activated T cells by a cell contact-dependent mechanism. The RPE cells inhibitory abilities were not affected by blocking of any of the tested surface molecules. The inhibition of the T cells' proliferation correlates with a decreased expression of IL2R-beta and -gamma chains. The T cells regain their ability to proliferate and increase their IL2R-beta and -gamma chain expression within 24 hr after removal from the coculture. It is concluded that the cultured human adult and foetal RPE cells inhibit the proliferation of activated T cells by a process that does not involve apoptosis. It depends on cell contact but the involved surface molecules were not revealed. The proliferation inhibition correlates with a modulation of the T cells' expression of IL2R, and is reversible.     

The Cultural Dimension in Childhood

This article emphasizes the fact that culture surrounds and influences the young people in child and youth care programs all the time, and that child and youth care workers must become cultural mediators for the culturally undernourished when assisting youth in care. This work must add to psychological pedagogics and social pedagogics a third new dimension, cultural pedagogics. Through raising and answering a series of six questions concerning culture, the author hopes to stimulate better practice and educational training in the cultural preparation of young people receiving child care services.     

Age-related macular degeneration: epidemiology and optimal treatment

Age-related macular degeneration (AMD) is a common macular disease affecting elderly people in the Western world. It is characterised by the appearance of drusen in the macula, accompanied by choroidal neovascularisation (CNV) or geographic atrophy. The disease is more common in Caucasian individuals than in pigmented races. In predominantly Caucasian populations, the age-standardised prevalence of AMD in at least one eye is 7760 cases per million. The age-standardised cumulated 1-year incidence of AMD in at least one eye is 1051 cases per million individuals. AMD is the most important single cause of blindness among Caucasian individuals in developed countries. Blindness resulting from AMD rarely occurs before age 70, and most cases occur after age 80. The age-standardised 1-year incidence of legal blindness resulting from AMD is 212 cases per million. Two-thirds of AMD cases have CNV (exudative cases); the remainder has only geographic atrophy. In cross-sectional population-based studies about 45% of eyes with AMD have visual acuity reduced to 20/200 or worse. This is true both for exudative AMD and pure geographic atrophy. Age and genetic predisposition are known risk factors for AMD. Smoking is probably also a risk factor. Preventive strategies using macular laser photocoagulation are under investigation, but their efficacy in preventing visual loss is as yet unproven. There is no treatment with proven efficacy for geographic atrophy. Optimal treatment for exudative AMD requires a fluorescein angiographic study and a physician capable of interpreting it. For CNV not involving the foveal centre, the only evidence-based treatment is laser photocoagulation. For AMD cases with subfoveal CNV, good visual acuity, and predominantly classic fluorescence pattern on fluorescein angiography, photodynamic therapy with verteporfin is the treatment of choice. Photodynamic therapy is also effective in eyes with pure occult CNV and evidence of recent disease progression. For new subfoveal CNV with poor vision and recurrent CNV, laser photocoagulation can be considered.     

Stimulation of spinal 5-HT(2A/2C) receptors potentiates the capsaicin-induced in vivo release of substance P-like immunoreactivity in the rat dorsal horn

Stimulation of spinal serotonin (5-HT)_2A/2C receptors has previously been reported to lead to either a pro-nociceptive or an anti-nociceptive response. Behavioral data have indicated that the pro-nociceptive effect is related to the release of substance P (SP). The aim of this in vivo microdialysis study was to investigate if stimulation of spinal 5-HT_2A/2C receptors by the selective agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) induces spontaneous or capsaicin-evoked increase in the release of SP-like immunoreactivity (SP-LI) in the rat dorsal horn. A dose of capsaicin (25 μM in the perfusion medium administered for 30 min), which did not lead to a significant release of SP-LI on its own, induced a significant increase of greater than 4-fold of the SP-LI level following spinal application of 50 nmol DOI. Higher (500 nmol) or lower (5 nmol) doses of DOI failed to induce a similar effect. In rats with a peripheral inflammation, induced by carrageenan, capsaicin (25 μM) induced a non-significant increase of SP-LI. A significant 8-fold increase of the SP-LI level was detected following administration of 50 nmol DOI in combination with capsaicin. The effect of DOI, which was completely prevented by co-administration of the 5-HT_2A receptor antagonist ketanserin in control animals without peripheral inflammation, was only partly blocked in animals with carrageenan induced peripheral inflammation. In conclusion, stimulation of 5-HT_2A/2C receptors facilitates the capsaicin-evoked release of SP-LI in the dorsal horn in both animals with and without carrageenan-induced unilateral inflammation. The observation that the highest dose of DOI failed to induce SP-LI release may be due to an inhibitory postsynaptic action at this dose.     

Posttraumatic stress disorder in first-time myocardial infarction patients

OBJECTIVES: The objectives of this study were to investigate the prevalence of posttraumatic stress disorder in patients with a first myocardial infarction compared with a random sample of healthy controls and to determine variables associated with the disorder. DESIGN: A questionnaire was distributed to 112 consecutive patients 4 to 6 weeks after infarction and to 115 healthy controls selected randomly from the general population. Objective clinical measures were obtained from the patients' medical records. RESULTS: Twenty-five (22%) patients qualified for a diagnosis of posttraumatic stress disorder (PTSD) compared with 8 (7%) controls with patients being more than a three-fold (OR: 3.84; 95% CI: 1.65 to 8.94) risk of having the disorder. When adjusting for other variables, the risk was reduced to above a two-fold risk (OR: 2.71; 95% CI: 0.99-7.41). In patients and controls, depression and neuroticism were associated with a diagnosis of PTSD adjusting for other variables. In patients, anxiety was associated with a diagnosis of PTSD adjusting for other variables. Left ventricular ejection fraction and symptoms of angina pectoris were not related to a diagnosis of PTSD in the patient group. CONCLUSIONS: Given that previous research has shown that persons with PTSD are at increased risk of cardiovascular diseases, cardiac patients with the disorder may be at a higher risk of recurrent cardiac events. Although longitudinal studies are needed to confirm such a relationship, this disorder should not be overlooked because of its potential role in reinfarctions and mortality.