Energetics of polymeric carbon monoxide.

The transformation of carbon monoxide (CO) from a molecular liquid to a polymeric solid under isothermal compression at room temperature is investigated using first principles theory. We report structural and thermodynamic properties from ambient density up to 2.45 g/cc obtained using density functional theory molecular dynamics simulations, including hybrid exchange corrections. The theoretical results are compared with newly obtained polymeric CO samples, synthesized in a large volume press. The explosive performance of polymeric CO is predicted and discussed. Under most favorable assumptions, it is found to be comparable to trinitrotoluene.

hPL deficiency with normal estriol levels in a normal pregnancy.

The third published case of human placental lactogen (hPL) deficiency in a normal pregnancy is reported. The results of the 3 cases are discussed. In all cases, estriol levels were normal and hPL levels were either unmeasurable or below 1 microgram/ml. The placenta showed no obvious abnormalities. Growth hormone and prolactin determinations did not contribute to the understanding of the deficiency; neither did the glucose levels in the maternal blood. All 3 infants were male.

Tumor immunogenicity--the prime determinant of the nutritional influence on the host-tumor relationship.

The influence which malnutrition plays on the host-tumor relationship is controversial because of the disparity of human and rodent tumors, a critical difference being the minimal immunogenicity of human tumors and the variable antigenicity of rodent tumors. The hypothesis we tested is that the influence of malnutrition on tumor growth is a result of the immunogenicity of the host's tumor. C-1300 neuroblastoma (NB) is an immunogenic tumor by in vivo and in vitro assessment while the histologically identical TBJ-NB clone is non-immunizing. Isogeneic A/J mice were malnourished with 2.5% protein chow and were inoculated with C-1300-NB or TBJ-NB; either serial tumor volumes were assessed by three-dimensional measurement or animals were serially killed and tumor weight/carcass weight ratios (TW/CW) were calculated. Non-immunogenic TBJ-NB grew more rapidly than C-1300-NB in both control and malnourished groups, but there was no difference in either tumor size or TW/CW ratios between the two TBJ-NB nutritional groups. Contrasting with these data were immunogenic C-1300-NB in that the tumor grew significantly better in malnourished mice (tumor volume p less than 0.05 day 12 and 14; TW/CW p less than 0.026 by day 21). Prior whole-body irradiation abrogated this difference. These data demonstrate that for tumors differing only in antigenicity the influence of malnutrition is on that tumor which induces an immunologic antitumor response.

Sinus histiocytosis with massive lymphadenopathy. Occurrence in identical twins with retroperitoneal disease.

Sinus histiocytosis with massive lymphadenopathy (SHML) was originally defined as a relatively specific benign pseudolymphomatous disorder. Although the etiology remains unknown, the spectrum of SHML has been expanded to include predominance of extranodal disease in some patients, clinically significant immunologic abnormalities in 10% of patients, and fatal outcome in 7% of patients. We report the rare occurrence of SHML in identical twins; to our knowledge, SHML in identical twins has been reported only once previously. The two patients described are also unusual because of the predominance of retroperitoneal disease with minimal peripheral adenopathy. After a seven-year clinical course, one twin died of extensive retroperitoneal disease, liver failure, bleeding diathesis, and seizure disorder. The other twin is alive after a six-year course of progressive retroperitoneal disease.

Neuroblastoma and nutritional support: influence on the host-tumor relationship.

The nutritional sequelae of neuroblastoma are secondary to tumor burden, tumor-host influenced metabolism, and antitumor operative, pharmacologic, and radiation therapy. Nutritional support and its influence on the outcome of clinical cancer is confusing; but in a defined murine system, we hypothesized that whether or not nutritional repletion favors the host-tumor relationship is dependent on a nutritional augmentation of host antitumor immunity. C1300 murine neuroblastoma (NB) elicits a host antitumor immune response as determined by in vivo and in vitro testing; but the TBJ clone of the same tumor is nonimmunogenic. After receiving two weeks of either regular 24% protein or protein restricted 2.5% protein chow, normal and malnourished mice received either C1300-NB or TBJ-NB and were serially followed to animal death. The median survival time (MST) of TBJ recipients was shorter in this more aggressive tumor, but the MST of 27.5 days was equal for normal and malnourished mice. Contrasting with these data were an MST of 38 days for malnourished C1300 NB recipients and an MST of 64.5 days for normally nourished C1300 NB recipients, values that are significantly different (P less than 0.02). These data suggest that nutritional support influencing host antitumor immunity may be of benefit only in that circumstance where the tumor elicits an antitumor immune response.

Timely immunization subverts the development of peripheral nonresponsiveness and suppresses tumor development in simian virus 40 tumor antigen-transgenic mice.

Tolerance to tumor cell-expressed molecules and selection of cells that evade immune surveillance during tumor progression create effective barriers to immunotherapy. We investigated the cytotoxic T-lymphocyte response to simian virus 40 (SV40) tumor (T/t) antigen in two lineages of transgenic mice bearing the same rat insulin promoter-SV40 T/t antigen (RIP Tag) hybrid gene. RIP1-Tag2 mice, which express Tag as embryos, are tolerant to Tag, whereas RIP1-Tag4 mice, which express the transgene in pancreatic islet beta cells several weeks after birth and develop insulinomas, can be immunized to generate active Tag-specific cytotoxic T lymphocytes as determined by in vitro assays. Indeed, RIP1-Tag4 mice immunized with Tag by SV40 infection prior to the time of endogenous transgene expression also mount an effective in vivo cellular immune response to the Tag-expressing pancreatic beta cells, and Tag-induced tumor growth is significantly delayed (up to 1 year). However, after the transgene is expressed, RIP1-Tag4 mice are unable to mount a tumor-inhibiting response upon immunization, although Tag-specific cytotoxic T cells can still be demonstrated in vitro. Our data suggest that Tag-specific T cells are rendered unresponsive in vivo in RIP1-Tag4 mice and that the establishment of this unresponsiveness to Tag can be prevented by SV40 immunization only before the onset of the transgene expression. In the older, successfully immunized mouse, decreased immune surveillance and selection of cells with down-regulation of major histocompatibility complex class I expression most likely set the stage for insulinoma development.

Osteosarcomas in transgenic mice expressing an alpha-amylase-SV40 T-antigen hybrid gene.

Mice of a transgenic mouse lineage 501, produced by zygotic injection of the parotid alpha-amylase promoter-SV40 T-antigen hybrid gene, developed osteosarcomas at about 15 months of age. The tumors predominantly involved the axial skeleton, were sometimes multiple, and metastasized to the liver. A cell line derived from a primary tumor produced osteosarcomas on transfer to nude mice. The 501 transgenic lineage thus provides a valuable new model for studying the histogenesis of osteosarcomas.

Positive-negative selection gene targeting with the diphtheria toxin A-chain gene in mouse embryonic stem cells.

The diphtheria toxin A-chain gene was used in a positive-negative selection gene targeting vector to alter the CD4 gene which is transcriptionally silent in mouse embryonic stem cells. Expression of the toxin gene was driven by a constitutively active enhancer, yet the targeting construct exhibited only minimal transient toxicity while enriching for targeted clones 9- to 29-fold. Germline transmission of the stem cell-derived genome was obtained. These data suggest the usefulness of this diphtheria toxin A-chain cassette in replacement-type positive-negative selection vectors. Its potential for novel applications, particularly in the enrichment for 'hit-and-run' insertion-type vectors, is discussed.

Immune effector mechanisms required for protection to rabies virus.

Genetically engineered mice with targeted mutations in genes encoding immunologically relevant molecules were used to elucidate the role of different immune effector mechanisms in protection against a rabies virus (RV) infection. In vaccinated animals challenged with a highly virulent strain of RV, antibodies were crucial in protection. In naive mice challenged with an attenuated strain of the virus that does not cause disease in adult fully immunocompetent mice but kills RAG mice that lack functionally active T and B cells, different immune effector mechanisms were shown to suffice for protection.