SV-IV,a major protein secreted from rat seminal vesicle epithelium,promotes lymphocyte cytotoxic activity against the lymphoblastoid Raji cell line in human peripheral blood mononuclear cells

The treatment of human peripheral blood mononuclear cells (PBMC) with micromolar concentrations of SV-IV, a major protein secreted from the rat seminal vesicle epithelium, promotes in this cell population a marked cytotoxic activity against the Raji lymphoblastoid cell line. This activity is apparently due to cell-to-cell contact interactions. The expression of HLA DR on Raji cells has a modulatory effect on the SV-IV-induced cytotoxic activity. The experimental evidence strongly suggests that the cytotoxic effector cells are functionally activated NK cells. Int. J. Cancer 72:321–328, 1997. © 1997 Wiley-Liss, Inc.     

Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1)

Iron is essential for all living organisms. Under normal conditions there is no regulatory and rapid iron excretion in humans and body iron levels are mainly regulated from the absorption of iron from the gut. Regular blood transfusions in thalassaemia and other chronic refractory anaemias can result in excessive iron deposition in tissues and organs. This excess iron is toxic, resulting in tissue and organ damage and unless it is removed it can be fatal to those chronically transfused. Iron removal in transfusional iron overload is achieved using chelation therapy with the chelating drugs deferoxamine (DF) and deferiprone (L1). Effective chelation therapy in chronically transfused patients can only be achieved if iron chelators can remove sufficient amounts of iron, equivalent to those accumulated in the body from transfusions, maintaining body iron load at a non-toxic level. In order to maintain a negative iron balance, both chelating drugs have to be administered almost daily and at high doses. This form of administration also requires that a chelator has low toxicity, good compliance and low cost. DF has been a life-saving drug for thousands of patients in the last 40 years. It is mostly administered by subcutaneous infusion (40-60 mg/kg, 8-12 h, 5 days per week), is effective in iron removal and has low toxicity. However, less than 10% of the patients requiring iron chelation therapy worldwide are able to receive DF because of its high cost, low compliance and in some cases toxicity. In the last 10 years we have witnessed the emergence of oral chelation therapy, which could potentially change the prognosis of all transfusional iron-loaded patients. The only clinically available oral iron chelator is L1, which has so far been taken by over 6000 patients worldwide, in some cases daily for over 10 years, with very promising results. L1 was able to bring patients to a negative iron balance at doses of 50-120 mg/kg/day. It increases urinary iron excretion, decreases serum ferritin levels and reduces liver iron in the majority of chronically transfused iron-loaded patients. Despite earlier concerns of possible increased risk of toxicity, all the toxic side effects of L1 are currently considered reversible, controllable and manageable. These include agranulocytosis (0.6%), musculoskeletal and joint pains (15%), gastrointestinal complaints (6%) and zinc deficiency (1%). The incidence of these toxic side effects could in general be reduced by using lower doses of L1 or combination therapy with DF. Combination therapy could also benefit patients experiencing toxicity with DF and those not responding to either chelator alone. The overall efficacy and toxicity of L1 is comparable to that of DF in both animals and humans. Despite the steady progress in iron chelation therapy with DF and L1, further investigations are required for optimising their use in patients by selecting improved dose protocols, by minimising their toxicity and by identifying new applications in other diseases of iron imbalance.     

Overexpression of nuclear NHERF1 in advanced colorectal cancer: association with hypoxic microenvironment and tumor invasive phenotype

Over 57% of colorectal cancer (CRC) patients have regional or distant spread of their disease at the time of diagnosis. Despite recent advances, there is a compelling need to better characterize prognostic markers for advanced CRC. The present study investigates protein expression of NHERF1, HIF-1α and TWIST1 and their relationship in distant normal mucosa (DNM), tumor (T) and adjacent normal mucosa (ANM), lymph node metastasis (LNM) and liver metastasis (LM), determining their role as potential markers in advanced stages of human CRC. Overexpression of nuclear NHERF1 was shown in 47% of tumors, which exhibited a significant association with poor histological grade (P=0.0346). Nuclear NHERF1 showed a higher expression in T, LNM and LM than both DNM (P<0.0001) and ANM (P<0.05). Nuclear HIF-1α was significantly higher in T, LNM and LM than DNM and ANM (P<0.05, P<0.001, P<0.0001, respectively). A positive correlation between nuclear NHERF1 and nuclear HIF-1α was found in LNM (r=0.331, P=0.020), where an extended co-localization of the two proteins was demonstrated. TWIST1 was more expressed in T than DNM and ANM (P<0.0001) and was higher in T than LNM and LM (P<0.0001). Moreover, nuclear NHERF1 was directly correlated to TWIST1 (r=0.339, P=0.015) in T samples, where a high co-expression of the two proteins was demonstrated both in no longer polarized epithelial cells and in invasive mesenchymal elements adjacent to hypoxic and perinecrotic colonic areas. Overall, nuclear NHERF1 expression was associated with poorer differentiation grade and with higher expression both of HIF-1α in lymphatic metastasis and TWIST1 in invasive front of tumor. Our results support the oncogenic role of NHERF1 and promote nuclear NHERF1 as a potential new biomarker of advanced CRC.     

Effective combination therapy of deferiprone and deferoxamine for the rapid clearance of excess cardiac IRON and the prevention of heart disease in thalassemia. The Protocol of the International Committee on Oral Chelators

The International Committee on Oral Chelators (ICOC) combination therapy protocol involving the administration of deferiprone (L1) during the day (80-110 mg/kg/day) and deferoxamine (DFO) (40-60 mg/kg at least 3 days/week) during the night for 8-12 hours using a pump, or the whole 24 hours using an elastomeric pump infuser, has been tested in 11 thalassemia patients (seven males, four females) over a period of 9-28 months. The patients had variable serum ferritin levels (0.54-4.6 mg/L) and cardiac iron load ranging from normal to severe siderosis levels (MRI T2*: 4.7-45 ms). There was a substantial overall reduction in serum ferritin levels (0.17-2.16 mg/L) and normalization of cardiac iron (MRI T2* >20 ms) in all patients. In two patients with severe and moderate cardiac iron load range levels, cardiac iron normalization was achieved within 9-10 months. Two patients on L1 monotherapy (80-120 mg/kg/day) maintained normal range MRI T2* cardiac iron levels over the same period. The ICOC combination therapy protocol appears to be the most effective and least cumbersome form of chelation treatment for the rapid clearance of excess iron from the heart.     

Effect of HBB genotype on survival in a cohort of transfusion-dependent thalassemia patients in Cyprus

Initiation of regular transfusion in transfusion-dependent thalassemia (TDT) is based on the assessment of clinical phenotype. Pathogenic HBB variants causing β-thalassemia are important determinants of phenotype and could be used to aid decision-making. We investigated the association of HBB genotype with survival in a cohort study in the four thalassemia centers in Cyprus. HBB genotype was classified as severe (β0/β0 or β+/β0), moderate (β+/β+), or mild (β0/β++ or β+/β++). Risk factors for mortality were evaluated using multivariate Cox proportional- hazards regression. Of the 537 subjects who were followed for a total of 20,963 person-years, 80.4% (95% confidence interval [95% CI]: 76.4-84.7) survived to 50 years of age with increasing rates of liver-, infectionand malignancy-related deaths observed during recent follow-up. We evaluated non-modifiable risk factors and found worse outcomes associated with male sex (hazard ratio 1.9, 95% CI: 1.1-3.0, P=0.01) and milder genotype (hazard ratio 1.6, 95% CI: 1.1-2.3, P=0.02). The effect of genotype was confirmed in a second model, which included treatment effects. Patients with a milder genotype initiated transfusion significantly later and had reduced blood requirements compared to those with moderate or severe genotypes, although pre-transfusion hemoglobin levels did not differ between genotypes. Our results suggest that early treatment decisions to delay transfusion and different long-term treatment strategies in individuals with milder genotypes have led to adverse longterm effects of under-treated thalassemia and worse survival. We propose that HBB genotype determination and use of this information to aid in decision-making can improve long-term outcomes of thalassemia patients.     

Descriptive analysis of malaria prophylaxis for travellers from Greece visiting malaria-endemic countries

International travel is changing the epidemiology of imported malaria. Our aim was to study malaria prophylaxis administered to travellers from Greece. The study was conducted during 2008-2009. Data were collected using a standardized form. A total of 2337 travellers were studied; prophylaxis was recommended to 60.2% of them. Of the 2337 travellers, 32.6% travelled to sub-Saharan Africa, 25.5% to South America, 11.8% to Indian subcontinent, 11.7% to Middle East, and 4.4% to Southeast Asia; prophylaxis was recommended to 77.4%, 64%, 80.6%, 4.8% and 73.5% of them, respectively. According to the purpose of travel, prophylaxis was recommended to 85.4% of those travelling for work, 75.2% of those visiting friends and relatives, and 62% of those travelling for recreation. Prophylaxis advised was provided to 68.5%, 66.2%, 61.5%, and 18.9% to those staying at a residence of local people, camping, hotels, and cruise ships, respectively. Regarding long-term travellers, malaria prophylaxis was recommended to 42.6%. Recommendation of malaria prophylaxis was significantly statistically in association with destination countries, purpose of travel, type of residence in endemic areas There is a need to improve recommendations for malaria prophylaxis for travellers from Greece, and to increase awareness and education of professionals providing travel health services in Greece.     

Novel 3-aryl-5-substituted-coumarin analogues: Synthesis and bioactivity profile

Eighteen 3-aryl-5-substituted-coumarins—six 5-acetyloxy-derivatives, six 5-hydroxy-derivatives, and six 5-geranyloxy-derivatives—were synthesized, structurally characterized and their antioxidant activity, lipoxygenase inhibitory ability, as well as their cytotoxic activity against human neuroblastoma SK-N-SH and HeLa adenocarcinoma cell lines were evaluated. The 5-acetyloxy-compounds 3a - 3f were found to be the best cytotoxic agents among all the compounds studied. The bromo-substituted coumarins 3a and 3b were remarkably active against HeLa cell line showing IC₅₀ 1.8 and 6.1 μM, respectively. Coumarin 5e possessing a geranyloxy-chain on position 5 of the coumarin scaffold presented dual bioactivity, while 5-geranyloxy-coumarin 5f was the most competent soybean lipoxygenase inhibitor of this series (IC₅₀ 10 μM). As shown by in silico docking studies, the studied molecules present allosteric interactions with soybean lipoxygenases.