Trends in template/fragment-free protein structure prediction

Predicting the structure of a protein from its amino acid sequence is a long-standing unsolved problem in computational biology. Its solution would be of both fundamental and practical importance as the gap between the number of known sequences and the number of experimentally solved structures widens rapidly. Currently, the most successful approaches are based on fragment/template reassembly. Lacking progress in template-free structure prediction calls for novel ideas and approaches. This article reviews trends in the development of physical and specific knowledge-based energy functions as well as sampling techniques for fragment-free structure prediction. Recent physical- and knowledge-based studies demonstrated that it is possible to sample and predict highly accurate protein structures without borrowing native fragments from known protein structures. These emerging approaches with fully flexible sampling have the potential to move the field forward

Mitotane reduces the chemoresistance phenotype in an adrenocortical carcinoma cell line

Adrenocortical carcinoma (ACC), a rare tumor, with incidence of 1–2 per million population annually, has a bimodal distribution by age, with cases clustering in children under 6, and in adults 30–40 years old. ACC has a dismal prognosis. The only curative treatment is complete surgical excision of the tumor, but late diagnosis prevents surgical cure, since ACC frequently recurs and metastasize. Chemotherapy is frequently ineffective, due to the overexpression of the MDR-1 gene, encoding for detoxifying pump P-gp, which confers chemoresistance to ACC. Mitotane, an adrenolitic drug, is being used as adjuvant therapy to prevent recurrence, despite several and important side effects appearing at therapeutic concentrations (14–20 mg/l; 40–60 mM). We aimed at identifying therapeutic strategies to overcome adrenocortical carcinoma chemoresistance by using mitotane. Human adrenocortical cells, NCI-H295R, expressing high P-gp levels, were treated with mitotane (2.5–80 mM) and doxorubicin (1–100 nM), identifying minimal cytotoxic concentrations. Cell viability and caspase 3/7 activity under 25 and 50 nM doxorubicin without or with 5 mM mitotane were tested. These drug concentrations are much lower than those reached in vivo. Combination treatments significantly and more potently reduced cell viability (40–60%) by inducing caspase-3/7 activity. In addition, we found that mitotane significantly reduced P-gp activity, promoting the intracellular accumulation of fluorescent compounds. Our results indicate that mitotane enhances the cytotoxic effects of doxorubicin in a chemoresistant adrenocortical carcinoma cell line, likely inhibiting P-gp activit

TRATTAMENTO DEL CARCINOMA PROSTATICO AVANZATO CON LO ZOLADEX, UN AGONISTA DELL'LHRH: RISULTATI DI UNO STUDIO MULTICENTRICO DI FASE II

Trattamento del carcinoma prostatico avanzato con lo Zoladex, un agonista dell'LHRH: risultati di uno studio multicentrico di fase II