Sensitization of multidrug resistant human ostesarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase

Chemotherapeutic agents have been used for the treatment of patients with osteosarcoma (OS). However, inherent or acquired resistance to these agents is a serious problem in the management of OS patients. The emergence of the multidrug resistance (MDR) phenotype in cancer cells is often associated with the overexpression of P-glycoprotein, encoded by the multidrug resistance gene MDR-1. The administration of some of the most common chemotherapeutic agents to these cells becomes ineffective because of their P-gp-driven efflux from the cell. Apo2L/TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines that is considered to induce death of cancer cells but not normal cells. Its powerful apoptotic activity is mediated through its cell surface death domain-containing receptors, TRAIL-R1/DR4 and TRAIL-R2/DR5, which in turn spread the signal in the cytosol through the activation of the caspase cascade. The Akt/PKB kinase is an important cell survival protein which is regulated by D3-phosphoinositides. High Akt expression and activity levels are well documented in many types of tumors, which very often show an altered PI3-K/Akt/PTEN pathway. In this study the U2OS human osteosarcoma cell line and its multidrug resistant (MDR) subline that overexpresses MDR-1 gene, MDR-U2OS, have been analyzed for their responsiveness to TRAIL. In conflict with the presence of active DR4 and DR5 receptors in both clones, U2OS cells exhibited only a low responsiveness to TRAIL, while the MDR-U2OS subline did exhibit a marked TRAIL sensitivity. An analysis of the post-receptor events showed that TRAIL responsiveness correlates with a reduced expression of endogenous Akt. In fact, expression in MDR-U2OS cells of a constitutively active Akt strongly decreased their sensitivity to TRAIL. The identification of Akt as a key modulator of TRAIL responsiveness could help to design TRAIL-based combinations for treatment of osteosarcoma. Moreover, the discovery that multidrug resistant osteosarcomas are highly sensitive to TRAIL-induced apoptosis indicates TRAIL as a new candidate for the treatment of multidrug resistant bone malignancies.     

New bis(pyridyl)methane derivatives from 4-hydroxy-2-pyridones: synthesis and antitumoral activity

Bis(pyridyl)methane derivatives 5-40 were obtained from the reaction of 4-hydroxy-2-pyridones 3 and 4 with aldehydes. Compounds 5-40 were evaluated for cytotoxic activity against a panel of 60 human cancer cell lines by the National Cancer Institute and some of them demonstrated inhibitory effects on the growth of a wide range of cancer cell lines generally at 10(-5) M level and in some case at 10(-7) M concentrations.     

Occupational risk factors for the sporadic form of Creutzfeldt-Jakob disease

Some case reports among European farmers and a few case-control studies suggested the hypothesis of an increased risk of the sporadic form of CJD (sCJD) associated with livestock farming or work as a butcher. Also, the discovery of the possibility of transmission of the disease via blood or by contact following corneal or dura madre transplant suggested that health occupations might also run higher sCJD risks. However, a meta-analysis of three case-control studies and a multicentre European study did not find any positive association between sCJD and health-related jobs or occupational contact with livestock, such as cattle and sheep, or animal products. To explore possible occupational risk factors for Creutzfeldt-Jakob disease (CJD), we used a publicly available US database including about 6 million deaths in 24 states during 1984-95. Cases were 636 deaths (300 men and 336 women) with CJD (ICD-9 code 046.1) as the underlying cause of death. Controls were 3,180 deaths randomly selected from among those who died from all other diseases except those affecting the central nervous system. CJD cases represented a wide variety of occupations (159) and industries (147). Among occupations and industries, for which previous reports suggested potential exposure to a transmissible spongiform encephalopathy (TSE) agent, the OR for CJD was significantly increased among butchers (OR = 6.8, 95% C.I. 1.5, 30.1, based on 4 cases and 3 controls), and persons working in offices of physicians (OR = 4.6, 95% C.I. 1.2, 17.6 based on 5 cases and 4 controls). Nine other occupations and seven other industries, for which no previous suggestion existed in the literature, also showed significant associations. Overall, our results suggest that occupational exposures are not an important source of sCJD infection. However, as the excess among butchers and some workers in health occupations was consistent with previous reports, more indepth research is warranted to address the hypothesis.     

Synthesis and antitumor evaluation of 6-thioxo-, 6-oxo- and 2,4-dioxopyrimidine derivatives.

A series of 6-thioxopyrimidines (5, 6), their 6-oxo- analogs (11-14), and pyrimidine-2,4-diones (20-26), were synthesized and evaluated for their antitumoral activity against 60 tumoral cell lines. The activity of propenethioamide (3, 4) and propeneamide (7-10 and 15-19) intermediates is also reported. Among the tested compounds the thioxopyrimidine 5c, bearing an N'-benzyl group, showed the best cytostatic activity. Furthermore, high selectivity and cytotoxic activity on the HOP-92 cell line of non-small cell lung cancer was exhibited by 3-amino-2-[(methylamino)thioxamethyl]-3-pyrrolidino-2-propenenitrile (3a).     

Synthesis and antimycobacterial activity of some isonicotinoylhydrazones

Aseries of isonicotinoylhydrazones 2 were prepared by addition of some aryloxyacetonitriles with isonicotinoylhydrazine in basic medium. These compounds have been further reacted with pyridinecarboxaldehydes to give the corresponding pyridylmethyleneamino derivatives 3–5. The new synthesized hydrazones and their pyridylmethyleneamino derivatives were tested for their activity against mycobacteria, Gram-positive and Gram-negative bacteria. The cytotoxicity was also tested. Several compounds showed a good activity against Mycobacterium tuberculosis H37Rv and some isonycotinoylhydrazones 2 showed a moderate activity against a clinically isolated M. tuberculosis which was isoniazid resistant.     

Clinical Operational Tolerance After Solid Organ Transplantation

Clinical operational tolerance (COT) is a clinical condition obtainable with difficulty after solid organ transplantation (SOT). It is characterized by perfectly normal graft function in the total absence of maintenance immunosuppression. Major benefits deriving from the onset of COT are the reduction of risk for immunosuppression-related side effects and the improved quality of life. Currently, COT can be safely achieved in stable liver transplant recipients; it remains a challenge after renal transplantation. Only 1 case of COT has been reported after lung transplantation; no cases have been described after other types of SOT. Overall, mechanisms of COT are unclear and strategies to induce COT cannot be applied on a regular base to a large cohort of SOT recipients. Due to the failure of molecularly based tolerogenic protocols, great hope relies in the adoption of cell-based strategies.     

Lymphadenopathy secondary to silicone hand joint prostheses

The occurrence of lymphadenopathies was investigated in 23 patients with diverse rheumatic conditions who had silastic prosthesis in joints of the hands, to determine whether these adenopathies were due to the presence of silicone particles. Five cases had clinically detectable lymph node enlargement and tissue samples were studied by light and scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDXA). In 3 out of the 5 cases foreign body granulomas were observed by light microscopy, SEM showing a highly irregular distribution of foreign body material with a peak for silicone by EDXA. Foreign body particle distribution closely correlated with silicone concentration. No granulomas were found in the two remaining patients with adenopathies who presented a non-specific reactive lymphadenitis. Our findings show that silicone lymphadenopathy is a more frequent complication (13%) of silastic arthroplasty than is usually recognized and therefore should be considered in the differential diagnosis of patients with lymph node enlargement who have previously received a silicone arthroplasty.