A polymorphism consisting of the presence or absence of a 250-bp DNA fragment was detected within the angiotensin I-converting enzyme gene (ACE) using the endothelial ACE cDNA probe. This polymorphism was used as a marker genotype in a study involving 80 healthy subjects, whose serum ACE levels were concomitantly measured. Allele frequencies were 0.6 for the shorter allele and 0.4 for the longer allele. A marked difference in serum ACE levels was observed between subjects in each of the three ACE genotype classes. Serum immunoreactive ACE concentrations were, respectively, 299.3 +/- 49, 392.6 +/- 66.8, and 494.1 +/- 88.3 micrograms/liter, for homozygotes with the longer allele (n = 14), and heterozygotes (n = 37) and homozygotes (n = 29) with the shorter allele. The insertion/deletion polymorphism accounted for 47% of the total phenotypic variance of serum ACE, showing that the ACE gene locus is the major locus that determines serum ACE concentration. Concomitant determination of the ACE genotype will improve discrimination between normal and abnormal serum ACE values by allowing comparison with a more appropriate reference interval.

/pdf/an-insertion-deletion-polymorphism-in-the-angiotensin-i-3m3dr1zdds.pdf

An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.

The ferritins: molecular properties, iron storage function and cellular regulation☆

https://www.cell.com/cell/pdf/0092-8674(88)90571-5.pdf

Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.

Many processes have been implicated in early atherogenesis. These include endothelial denudation, injury, or activation, including shear stress–related events; local adherence of platelets; lipoprotein oxidation; lipoprotein aggregation; macrophage chemotaxis and foam cell formation; and smooth muscle cell alterations. Which process, if any, could be regarded as the key event in early atherogenesis, ie, absolutely required, yet also sufficient as the sole pathological stimulus in an otherwise normal artery to provoke a cascade of events leading to lesion formation? The work of many investigators, which we summarize here, strongly supports subendothelial retention of atherogenic lipoproteins as the central pathogenic process in atherogenesis (for prior reviews, see References 1 through 61 2 3 4 5 6 ). Our thesis is that other contributory processes are either not individually necessary or are not sufficient. Most often, they are merely normal, expected responses of otherwise-healthy tissue to the presence of retained lipoproteins.

It is instructive to catalog other processes that have been argued to be central to the initiation of atherogenesis. The first is endothelial denudation,7 8 9 injury,10 or activation,11 12 as outlined in the “response-to-injury” hypothesis of Ross, Glomset, and coworkers. Although this important hypothesis has stimulated much of the work that we cite here, there is no definitive evidence in vivo that endothelial injury is either necessary or sufficient for lesion formation.

The response-to-injury hypothesis originally presupposed endothelial desquamation as the key event in atherogenesis.7 8 9 It is now clear, however, that developing atheromata are covered by an intact endothelial layer throughout most stages of lesion progression: lipoprotein retention, fatty streak formation, and formation of advanced lesions.5 6 12 13 14 15 In humans, only the most complicated, ulcerated lesions lose their endothelial layer. Furthermore, in some experimental models, an intact endothelium is required …

The Response-to-Retention Hypothesis of Early Atherogenesis

Extensive research over the past 30 years has revealed the involvement of Ras not only in tumorigenesis but also in many developmental disorders. The complexity of the molecular and cell biological mechanisms of action of Ras proteins indicates that much remains to be learnt.

Ras oncogenes: split personalities

Monoclonal antibodies to membrane antigens of human small cell carcinoma of the lung were produced by fusion of P3X63/Ag8U1 mouse myeloma cells with spleen cells from BALB/c mice immunized against the intact cells of the small cell carcinomas grown in BALB/c nude mice. The hybrids were screened for antibody production using intact cells in a solid-phase radioimmunoassay or in a membrane fluorescence with a fluorescence-activated cell sorter. Four monoclonal antibodies were chosen that demonstrated reactivities with human small cell carcinoma of the lung and not with apparently normal diploid fibroblasts or lymphoblastoid cells. The antibodies designated as TFS-1 and TFS-2 rather demonstrated "pancarcinoma" reactivity, showing binding to the other types of lung cancer (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) and carcinomas derived from other organs, such as colon, pancreas, or stomach. The monoclonal antibodies TFS-3 and TFS-4 preferentially bound to small cell carcinoma cells and neuroblastoma cells, but not to non-small cell carcinomas (adenocarcinoma, squamous cell, or large cell). Especially, TFS-4 did not bind to a variety of other normal or malignant cells. Immunoprecipitation of the antigens by monoclonal antibodies and sodium dodecyl sulfate:polyacrylamide gel electrophoresis revealed that they had different molecular weights.

Monoclonal antibodies to surface antigens of small cell carcinoma of the lung

Recombinant human granulocyte colony-stimulating factor (G-CSF) was prepared and its granulopoietic effects on mice were examined. When mice were injected intraperitoneally with the G-CSF daily for 14 days, marked granulocytosis occurred in the mice. The number of progenitor cells (CFU-C) was remarkably increased in the spleen. The results suggest that G-CSF plays a central role in granulocyte production in vivo.

Recombinant human granulocyte colony-stimulating factor induces granulocytosis in vivo.

Transforming genes in human leukemia cells

Activation of the c-K-ras oncogene in a human pancreas carcinoma

Two different types of lung cancer, a squamous cell carcinoma designated as OTUK, and an undifferentiated large cell carcinoma named as T3M-10, were investigated in vitro; both produced a moderate neutrophilia in each patient. In order to analyze this phenomenon, primary cultures were performed. Epithelial cells attached and grew in both of the cultures. The conditioned medium from both tumor cells revealed high colony-stimulating-factor (CSF) activities. From T3M-10 tumor cultures, a new CSF-producing cell line has been established. T3M-10 cells have been continuously propagated during the last 28 months and produced CSF. Chromosomal analysis revealed the cell line to be a human aneuploid one with a near-diploid mode. These results indicate that the two different types of lung cancers produce CSF, which may have stimulated granulopoiesis in vivo in the patients as well.

Michio Fujisawa

Papers

Monoclonal antibodies to surface antigens of small cell carcinoma of the lung

Recombinant human granulocyte colony-stimulating factor induces granulocytosis in vivo.

Transforming genes in human leukemia cells

Activation of the c-K-ras oncogene in a human pancreas carcinoma

Establishment of a human colony-stimulating-factor-producing cell line from an undifferentiated large cell carcinoma of the lung.