Excessive tumor-elaborated VEGF and its neutralization define a lethal paraneoplastic syndrome.

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and key regulator of both physiologic and pathologic (e.g., tumor) angiogenesis. In the course of studies designed to assess the ability of constitutive VEGF to block tumor regression in an inducible RAS melanoma model, mice implanted with VEGF-expressing tumors sustained high morbidity and mortality that were out of proportion to the tumor burden. Documented elevated serum levels of VEGF were associated with a lethal hepatic syndrome characterized by massive sinusoidal dilation and endothelial cell proliferation and apoptosis. Systemic levels of VEGF correlated with the severity of liver pathology and overall clinical compromise. A striking reversal of VEGF-induced liver pathology and prolonged survival were achieved by surgical excision of VEGF-secreting tumor or by systemic administration of a potent VEGF antagonist (VEGF-TRAP(R1R2)), thus defining a paraneoplastic syndrome caused by excessive VEGF activity. Moreover, this VEGF-induced syndrome resembles peliosis hepatis, a rare human condition that is encountered in the setting of advanced malignancies, high-dose androgen therapy, and Bartonella henselae infection. Thus, our findings in the mouse have suggested an etiologic role for VEGF in this disease and may lead to diagnostic and therapeutic options for this debilitating condition in humans.

Histone patterns during early embryogenesis in the euchiuroid Urechis caupo.

Histones were isolated from nuclei of Urechis caupo unfertilized eggs and embryos from early cleavage through gastrula. Polyacrylamide gel electrophoresis showed the presence of a slow migrating H1s fraction in the egg which was replaced by a faster migrating H1 during development. Radioactive labelling showed no synthesis of H1s from fertilization up to gastrula and a high rate of synthesis of H1 relative to the other histones during cleavage and blastula stages.

Ultrastructural studies on spermatogenesis in a sex-ratio-mutant strain of Drosophila simulans.

The aberrant sex-ratio mutation in D. simulans used for this study is a temperature-sensitive autosomal recessive. Homozygous males raised at 16 degrees C produce about 2% of F1, but those raised at 26 degrees C, have a normal sex ratio. Ultrastructural studies of spermatogenesis have revealed many anomalies in the germ cells of flies raised at 16 degrees C, but the same flies raised at 26 degrees C had few anomalies. The earliest spermatogenic stage with noticeable abnormalities was the primary spermatocyte. In later stages there were pronounced abnormalities in nucleoli, chromatin condensation, nuclear shape, Golgi complex, acrosome, and microtubules. There is asynchronous differentiation of spermatids within a bundle. Some of the abnormalities encountered are disorganization or loss of microtubules of the axoneme, degenerating nebenkern derivatives, and increased numbers of lysosomes, multilamellate bodies, and multivesicular bodies. At the lower temperature, more than half of the sperm within the same bundle were found in different stages of degeneration. Genetic analysis suggests that the sex-ratio gene causes abnormalities and degeneration of most of the Y-bearing sperm. However, counts of abnormal sperm at the ultrastructural level indicate that some X-bearing sperm must also undergo degeneration. These observations show that the sex-ratio gene is of variable penetrance at different temperatures in the primary spermatocyte and of differential penetrance in X- and Y-bearing sperm.

Sites of synthesis and processing of ribosomal RNA presurosrs within the nucleolus of Urechis caupo eggs.

Nucleoli from unfertilized Urechis eggs, labeled with tritiated RNA precursors, have been isolated for simultaneous autoradiographic localization and biochemical analysis of labeled RNA. The production of the ribosomal RNA precursor (38S) and its first cleavage occur at the fibrillar core region of the nucleolus. The products, predominantly 30S RNA, are then rapidly transported and stored in the granular cortex of the nucleolus. The formation of the nucleolar cortex, therefore, seems to result from an accumulation of partially processed ribosomal RNA with its associated proteins.

Evidence for control of the rate of nuclear DNA synthesis by the nuclear membrane in eukaryotic cells.

Rates of DNA synthesis in root tip cells of diploid and autotetraploid snapdragon (Antirrhinum majus) seedlings and in diploid and tetraploid (mononucleate and bidiploid-nucleate) regenerating mouse-liver cells have been studied. The increase in this rate in the tetraploid cells is closely correlated with the increase in nuclear surface area, but not with the nuclear volume; this suggests a possible control of the rate of DNA synthesis by the nuclear membrane.