PEG-3, a nontransforming cancer progression gene, is a positive regulator of cancer aggressiveness and angiogenesis

Cancer is a progressive disease culminating in acquisition of metastatic potential by a subset of evolving tumor cells. Generation of an adequate blood supply in tumors by production of new blood vessels, angiogenesis, is a defining element in this process. Although extensively investigated, the precise molecular events underlying tumor development, cancer progression, and angiogenesis remain unclear. Subtraction hybridization identified a genetic element, progression elevated gene-3 (PEG-3), whose expression directly correlates with cancer progression and acquisition of oncogenic potential by transformed rodent cells. We presently demonstrate that forced expression of PEG-3 in tumorigenic rodent cells, and in human cancer cells, increases their oncogenic potential in nude mice as reflected by a shorter tumor latency time and the production of larger tumors with increased vascularization. Moreover, inhibiting endogenous PEG-3 expression in progressed rodent cancer cells by stable expression of an antisense expression vector extinguishes the progressed cancer phenotype. Cancer aggressiveness of PEG-3 expressing rodent cells correlates directly with increased RNA transcription, elevated mRNA levels, and augmented secretion of vascular endothelial growth factor (VEGF). Furthermore, transient ectopic expression of PEG-3 transcriptionally activates VEGF in transformed rodent and human cancer cells. Taken together these data demonstrate that PEG-3 is a positive regulator of cancer aggressiveness, a process regulated by augmented VEGF production. These studies also support an association between expression of a single nontransforming cancer progression-inducing gene, PEG-3, and the processes of cancer aggressiveness and angiogenesis. In these contexts, PEG-3 may represent an important target molecule for developing cancer therapeutics and inhibitors of angiogenesis.

Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma.

Kaposi sarcoma (KS) is the leading neoplasm of HIV-infected patients and is also found in several HIV-negative populations. Recently, DNA sequences from a novel herpesvirus, termed KS-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV-8) have been identified within KS tissue from both HIV-positive and HIV-negative cases; infection with this agent has been proposed as a possible factor in the etiology or pathogenesis of the tumor. Here we have examined the pattern of KSHV/HHV-8 gene expression in KS and find it to be highly restricted. We identify and characterize two small transcripts that represent the bulk of the virus-specific RNA transcribed from over 120 kb of the KSHV genome in infected cells. One transcript is predicted to encode a small membrane protein; the other is an unusual polyadenylylated RNA that accumulates in the nucleus to high copy number. This pattern of viral gene expression suggests that most infected cells in KS are latently infected, with lytic viral replication likely restricted to a much smaller subpopulation of cells. These findings have implications for the therapeutic utility of currently available antiviral drugs targeted against the lytic replication cycle.

Amino-terminal protein-protein interaction motif (POZ-domain) is responsible for activities of the promyelocytic leukemia zinc finger-retinoic acid receptor-alpha fusion protein.

Promyelocytic leukemia zinc finger-retinoic acid receptor a (PLZF-RARalpha), a fusion receptor generated as a result of a variant t(11;17) chromosomal translocation that occurs in a small subset of acute promyelocytic leukemia (APL) patients, has been shown to display a dominant-negative effect against the wild-type RARalpha/retinoid X receptor alpha (RXRalpha). We now show that its N-terminal region (called the POZ-domain), which mediates protein-protein interaction as well as specific nuclear localization of the wild-type PLZF and chimeric PLZF-RARalpha proteins, is primarily responsible for this activity. To further investigate the mechanisms of PLZF-RARalpha action, we have also studied its ligand-receptor, protein-protein, and protein-DNA interaction properties and compared them with those of the promyelocytic leukemia gene (PML)-RARalpha, which is expressed in the majority of APLs as a result of t(15;17) translocation. PLZF-RARalpha and PML-RARalpha have essentially the same ligand-binding affinities and can bind in vitro to retinoic acid response elements (RAREs) as homodimers or heterodimers with RXRalpha. PLZF-RARalpha homodimerization and heterodimerization with RXRalpha were primarily mediated by the POZ-domain and RARalpha sequence, respectively. Despite having identical RARalpha sequences, PLZF-RARalpha and PML-RARalpha homodimers recognized with different affinities distinct RAREs. Furthermore, PLZF-RARalpha could heterodimerize in vitro with the wild-type PLZF, suggesting that it may play a role in leukemogenesis by antagonizing actions of not only the retinoid receptors but also the wild-type PLZF and possibly other POZ-domain-containing regulators. These different protein-protein interactions and the target gene specificities of PLZF-RARalpha and PML-RARalpha may underlie, at least in part, the apparent resistance of APL with t(11;17) to differentiation effects of all-trans-retinoic acid.

Pedro Gutiérrez Bueno (1745-1822), los libros de texto y los nuevos públicos de la química en el último tercio del siglo XVIII

El presente trabajo se enmarca en un proyecto de investigación acerca del papel de las prácticas y los conocimientos químicos en la transición de la materia médica a la farmacología experimental. Dentro de ese esquema general, el objeto de este artículo es el estudio de los libros de texto destinados a los estudiantes de medicina y de cirugía durante los años finales del siglo XVIII y la primera mitad del siglo XIX. En un estudio anterior, publicado en esta revista nos ocupamos de establecer las coordenadas institucionales generales dentro de las cuales fueron escritas, publicadas y leídas estas obras. Este trabajo es una continuación del anterior y está dedicado al análisis del «Curso de química» de Pedro Gutiérrez Bueno. A través de esta obra, se intenta ofrecer nuevos datos sobre los nuevos públicos de la química a finales del siglo XVIII y su influencia en la estructura y contenidos de los nuevos libros de texto.

Engineer Leandro Badarán’s project to safeguard the fortresses of Alicante in 1794

After the construction of the San Carlos bastion in Alicante in the final decade of the seventeenth century, and the great trench which the English built around the district of San Francisco during their years of dominance in the War of Succession, the waters of the San Blas gully caused serious damage to these fortifications of the city and to the trade buildings of the port. In 1772, the diversion canal was built. It was designed to divert the riverbed of the gully and send the waters directly to the sea. The project had been initially designed by the Engineer General, Jorge Próspero de Verboom in 1721. This unique work of engineering had some defects, principally in the breakwater which prevented the waters from flowing down the former river course. On several occasions, the water returned to its original riverbed due to the weakness of the breakwater, the narrowness of the channel’s bed and its lack of regularisation, causing serious damage to the bastion, the Babel-facing façade, the traders’ warehouses and other buildings. This study describes the project that the military engineer Leandro Badarán carried out in 1794 in order to technically improve this canal and examines his report on the state of the fortifications. Similar works built in Spain are also explained. It also analyses the repeated disputes between the war department and the port throughout these years over finding a technical solution to the problem.

Letter from William Croswell to George Richards, 1794 September 1

One-page letter from Croswell to George Richards, the Pastor of the Universal Society in Portsmouth, New Hampshire, requesting information about teaching opportunities in the area.

Letter from George Richards to William Croswell, 1794 September 5

One leaf containing the response of Pastor George Richards to Croswell's September 1, 1794, request for information on teaching opportunities.

Payment order for Theodore Dehon, 1794 September 26

Handwritten order to John Sale to pay scholarship funds to Theodore Dehon for use by his son Theodore Dehon (Harvard AB 1795), signed by John Clarke, David Tilden, and James Morrill.

Audited accounts, 1713-1745

The parchment-bound hardcover folio volume contains the Steward's accounts with the College from March 20, 1712/13 through August 9, 1745. The accounts are arranged as Harvard College's debits to the Steward with entries listing the Steward's expenses for students, salaries, and provisions and equipment, and the Steward's credits collected from the quarterly bills, arranged by type of charge (such as study rent, payments from the Butler, and repairs).

Accounts with Harvard College, 1733-1745

The paper covered notebook contains the Steward's accounts with Harvard College kept by Steward Andrew Bordman II from 1733-1745.

Accounts with Harvard College, 1745-1753, 1764

The folio-sized paper covered notebook contains Steward Andrew Bordman III's accounts with Harvard College from 1745-1753. The final page of text, signed on September 19, 1764 by Bordman's son, Andrew Bordman IV, settles the accounts.

Quarter bills for Samuel Stearns signed by Steward Caleb Gannett, 1793-1794

Six printed quarter bills for Samuel Stearns (Harvard AB 1794) with Steward and Commons, Sizings, Study and Cellar Rent, Instruction, Library, French Instruction, Medical Instruction, Books, Sweepers, Catalogues and Commencement Dinner, Repairs, Wood, and Punishment totals. Bills signed by Steward Caleb Gannett.