Changes of topoisomerase IIalpha expression in breast tumors after neoadjuvant chemotherapy predicts relapse-free survival.

PURPOSE: To assess the value of changes in the expression of topoisomerase IIalpha (TopoII) and the proto-oncogene erbB-2 (HER-2) as predictors of relapse-free survival in women with operable breast cancer treated with anthracycline-based neoadjuvant chemotherapy. PATIENTS AND METHODS: Seventy-seven patients with primary breast cancer who had undergone neoadjuvant anthracycline-based chemotherapy were included in the present study. TopoII and HER-2 were measured by immunohistochemistry in prechemotherapy and postchemotherapy (at the time of surgery) tumor specimens, and the value of their changes as predictors of relapse-free survival were evaluated by Kaplan-Meier and Cox proportional hazard regression analyses. RESULTS: Neoadjuvant chemotherapy resulted in a significant reduction in the percentage of cells expressing TopoII (P < 0.0001). No significant change was observed for HER-2. TopoII and HER-2 expression before chemotherapy predicted tumor response to treatment. Changes in TopoII expression after chemotherapy were strongly associated with a poor relapse-free survival (P < 0.0001) in a Cox multivariate analysis adjusted for other clinicopathologic prognostic factors. CONCLUSION: Changes in TopoII expression after anthracycline-based neoadjuvant chemotherapy is an independent predictor of a poor relapse-free survival in patients with breast cancer. Tumor cells displaying an increased TopoII expression after treatment may be responsible for relapses, and may, therefore, define a group of patients with anthracycline-resistant breast cancer.     

Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased Raf-1 ubiquitin-dependent degradation

The multi-drug combination of oxaliplatin (OXA), 5-Fluorouracil (5-FU) and leucovorin (LF) is currently considered as the gold standard treatment for metastatic colorectal carcinoma. In previous studies, we have studied a chemotherapy regimen containing gemcitabine (GEM), OXA, LF, and 5-FU (named GOLF regimen) that has shown a good safety profile and highly significant anti-tumor activity. In the present study, we have investigated on the anti-tumour mechanisms of GOLF in human colon cancer HT-29 and WiDr cell lines. We have found that GOLF induced growth inhibition that was largely caused by apoptosis differently from other combinations. Moreover, the different drugs composing GOLF were highly synergistic in inducing growth inhibition. Apoptosis induced by GOLF combination was paralleled by PARP cleavage and caspase 9 and 3 activation that were not recorded in the other combinations. An about 85% decrease of the activity of Erk and Akt was found in GOLF-treated cells. These effects were likely due to decreased expression of the upstream activator Raf-1 and of Akt itself, respectively. The intracellular levels of these signalling components can be post-translationally regulated by ubiquitin-dependent degradation through proteasome. Therefore, we have evaluated the expression of some chaperone components and we have found that GOLF did not affect the expression of both heat shock protein (HSP) 90 and 27 but induced an about 90% increase of HSP70 levels suggesting the inactivation of the multi-chaperone complex. Moreover, an about 4-fold increase of the ubiquitination of Raf-1 was also found and the addition for 12 h of 10 microM proteasome inhibitor lactacystin caused an accumulation of the ubiquitinated isoforms of Raf-1. In conclusions, GOLF was a combination highly synergistic in inducing both growth inhibition and apoptosis of colon cancer cells. These effects likely occurred through the disruption of critical survival pathways and the inactivation of multi-chaperone complex.     

Application of the RICEWQ-VADOFT model for simulating the environmental fate of pretilachlor in rice paddies

No validated models in Europe are capable of simulating the environmental fate of pesticides under the specific conditions of rice fields. Rice water quality--vadose zone flow and transport (RICEWQ-VADOFT) is a model developed from the coupling of a surface runoff model (RICEWQ) and a vadose zone flow and transport model (VADOFT) for determining predicted environmental concentrations in paddy water and sediment, runoff, and groundwater. This study is intended to evaluate the capability of this model to simulate effectively the environmental fate of the herbicide pretilachlor in the paddy environment. A two-year field study conducted in a representative rice-cultivated area of northern Italy provided measured concentrations of pretilachlor in paddy water and sediment and also a limited number of observations on runoff losses. The model successfully predicted the water balance in the paddy field in both years. After limited calibration, the model predicted the fate of pretilachlor in paddy water and sediment with high accuracy. Agreement between predicted and measured concentrations of pretilachlor in both years was assessed statistically using several statistical indicators. For example, modeling efficiency (EF) values of 0.867 to 0.935 and 0.702 to 0.718 in paddy water and sediment, respectively, document the strong agreement between predicted and measured pesticide concentrations. The model predictions showed high agreement with the limited amount of measured runoff data in 2002. The model predicted that no significant amounts of pretilachlor would leach below the top 25 cm of the soil, although no measured data were available to evaluate the predicted results. A sensitivity analysis of the model to variables controlling pesticide partitioning to paddy sediment (VBIND, depth for direct partitioning of pesticide to bed sediment; VMIX, mixing velocity by molecular diffusion) revealed that the predictions of pesticide leaching were influenced strongly by those variables. Generally the RICEWQ-VADOFT model is a useful modeling tool for pesticide risk assessment in rice paddies.     

Accumulation of dolichol in older tissues satisfies the proposed criteria to be qualified a biomarker of aging

Criteria for defining biomarkers have been suggested. Accumulation of dolichol in tissues of older animals meets the following criteria: (a) levels of dolichol exhibit a quantitative correlation with age in all tissues and are not altered by several age-dependent diseases in the same direction as that of aging; (b) accumulation is not secondary to metabolic changes of aging and is altered appropriately by factors that modulate the aging rate like caloric restriction and physical exercise; (c) biomarker is applicable to different tissues across mammalian species, including humans, and to trisomy 21 and its hypothalamic digoxin-mediated model. Reliable changes in tissue dolichol levels are seen in relatively short intervals of time compared to over a life span, and levels can be tested on a small amount of tissue without causing death of the animal. In this article, we show applications to the study of host-graft interaction and detection of gender-related differences in biological age, and we discuss mechanism(s) of accumulation.     

Subclinical hypothyroidism in a patient affected by advanced AIDS and visceral leishmaniasis

Hypothyroidism has been shown to occur in HIV disease. Thyroid function of patients affected by AIDS and leishmaniasis is unknown. Here we report the case of an AIDS advanced patient developing hypothyroidism during leishmaniasis. The thyroid disorder might have been caused by infiltration of the gland by Leishmania. An additive impact of HIV in thyroid function impairment is suggested.     

Inter-rater reliability of the EEG reading in patients with childhood idiopathic epilepsy

The level of agreement in the interpretation of EEG records by different experienced readers working in three child neurology tertiary centers has been evaluated. EEG recordings randomly chosen from patients with idiopathic epilepsy were included. Optimal or suboptimal agreement was found for presence of ictal and interictal discharges. Contrary to ictal discharges, the distribution and location of interictal discharges was not unanimously interpreted and agreement was unsatisfactory when assessing the background activity.     

Blood pressure control and risk of stroke in untreated and treated hypertensive patients screened from clinical practice: results of the ForLife study

OBJECTIVES: Stroke has a high prevalence in Italy, and is the third cause of death worldwide. Hypertension is the most important risk factor contributing to the risk of stroke. The aims of this study were to assess the risk of stroke in a large cohort of hypertensive patients, and to determine the percentage with controlled blood pressure, to establish the contribution of this factor to the risk of stroke. METHODS: The study involved general practitioners to make it representative of clinical practice. They were asked to recruit 10 consecutive hypertensive patients, treated and untreated. Data collection included a full medical history and a physical examination. The 10-year absolute risk of stroke was calculated by an algorithm derived, with some modification, from the Framingham study. RESULTS: Most untreated hypertensive patients were grade 1 or 2. In treated hypertensive patients, controlled blood pressure values occurred in 18.4%, the percentage being less in patients with left ventricular hypertrophy and diabetes. In diabetic hypertensive patients the more stringent blood pressure control recommended by the guidelines was achieved in only 3.0% of cases. The average 10-year stroke risk was 17%, a greater risk being more common in elderly patients, diabetic individuals and in those with left ventricular hypertrophy. CONCLUSION: Current antihypertensive treatment achieved blood pressure control in a limited fraction of hypertensive patients seen by general practitioners. The risk of stroke in hypertensive patients is by no means negligible, which emphasizes the need for more attention to be paid to the prevention of this disease.