Evolution of two actin genes in the sea urchin Strongylocentrotus franciscanus

The complete nucleotide sequences of two chromosomally linked actin genes from the sea urchin Strongylocentrotus franciscanus are presented. The genes are separated by 5.7 kilobases, occur in the same transcriptional orientation, and contain introns in identical positions. The structures and nucleotide sequences of the two genes are extremely similar, suggesting that they arose through a recent duplication. Comparison of the nucleotide sequences of the genes allows inferences to be made about mutational mechanisms active since the duplication event. Whereas point mutations predominate in the coding regions, the introns and flanking DNA are more heavily influenced by a variety of events that cause simultaneous changes in short regions of DNA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48040/1/239_2005_Article_BF02101689.pd

Optimization of antitrypanosomatid agents: identification of nonmutagenic drug candidates with in vivo activity

Chagas disease, caused by Trypanosoma cruzi parasite, was described thousands of years ago. Currently, it affects millions of people, mostly in Latin America, and there are not suitable drugs for treating it. As an attempt to find appropriate drugs to deal with this problem, we report here on the design, synthesis and characterization of eighty-two new compounds. Trypanosomicidal behavior in vitro showed more than twenty outstanding derivatives with anti-Trypanosoma cruzi activity. Furthermore, we studied the nonspecific toxicity against mammalian cells determining their selectivity and also performed mutagenicity studies. Proof of concept, in vivo studies, was conducted with two of the most promising derivatives (77 and 80). They were identified as candidates because they have: (i) very simple and cost-effective syntheses; (ii) activity against different stages and strains of the parasite showing excellent in vivo behavior during the acute phase of Chagas disease; (iii) neither nonspecific toxicity nor mutagenic activity.Fil: Guzmán Álvarez, Javier Varela. Universidad de la República; UruguayFil: Varela, Javier. Universidad de la República; UruguayFil: Márquez, Pablo. Universidad de la República; UruguayFil: Gabay, Martín. Universidad de la República; UruguayFil: Arias Rivas, Carmen Elena. Centro Nacional de Investigaciones Científicas; El SalvadorFil: Cuchilla, Karina. Centro Nacional de Investigaciones Científicas; El SalvadorFil: Echeverría, Gustavo Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Piro, Oscar Enrique. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Chorilli, Marlus. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Leal, Sandra M.. Universidad Industrial Santander; ColombiaFil: Escobar, Patricia. Universidad Industrial Santander; ColombiaFil: Serna, Elva. Universidad Nacional de Asunción; ParaguayFil: Torres, Susana. Universidad Nacional de Asunción; ParaguayFil: Yaluff, Gloria. Universidad Nacional de Asunción; ParaguayFil: Vera de Bilbao, Ninfa I.. Universidad Nacional de Asunción; ParaguayFil: González, Mercedes. Universidad de la República; UruguayFil: Cerecetto, Hugo. Universidad de la República; Urugua

Toward a Drug Development Path That Targets Metastatic Progression in Osteosarcoma

Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a "Perspective" that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting

Toward a drug development path that targets metastatic progression in osteosarcoma

Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a "Perspective" that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting

Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models

Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival is poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis, although its functional importance has not been defined. Here, we report the identification of mutations in FGFR4 in human RMS tumors that lead to its activation and present evidence that it functions as an oncogene in RMS. Higher FGFR4 expression in RMS tumors was associated with advanced-stage cancer and poor survival, while FGFR4 knockdown in a human RMS cell line reduced tumor growth and experimental lung metastases when the cells were transplanted into mice. Moreover, 6 FGFR4 tyrosine kinase domain mutations were found among 7 of 94 (7.5%) primary human RMS tumors. The mutants K535 and E550 increased autophosphorylation, Stat3 signaling, tumor proliferation, and metastatic potential when expressed in a murine RMS cell line. These mutants also transformed NIH 3T3 cells and led to an enhanced metastatic phenotype. Finally, murine RMS cell lines expressing the K535 and E550 FGFR4 mutants were substantially more susceptible to apoptosis in the presence of a pharmacologic FGFR inhibitor than the control cell lines expressing the empty vector or wild-type FGFR4. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncogene, and these are what we believe to be the first known mutations in a receptor tyrosine kinase in RMS. These findings support the potential therapeutic targeting of FGFR4 in RMS