Fulminant myocarditis owing to high-dose interleukin-2 therapy for metastatic melanoma.

High-dose interleukin-2 (IL-2) therapy may cause acute myocarditis characterised by diffuse myocardial involvement and occasionally fulminant heart failure. Cardiac MRI (CMRI) provides a comprehensive assessment of myocardial function, inflammation and injury in a single examination and has shown value in the diagnosis of myocarditis. We report a case of a 54-year-old male with metastatic melanoma who developed acute severe myocarditis with fulminant heart failure after high-dose IL-2 therapy. CMRI using a combination of T(2) weighted imaging and T(1) weighted late post-gadolinium enhancement techniques played a key role in establishing the diagnosis. To our knowledge we present the first case report of the combined use of T(1) and T(2) weighted CMRI techniques to diagnose IL-2 induced myocarditis.

Proliferation, hormonal responsiveness, and estrogen receptor content of MCF-7 human breast cancer cells grown in the short-term and long-term absence of estrogens.

We have examined the effect of short-term and long-term growth in the absence of estrogens on the proliferation rate and estrogen and antiestrogen responsiveness of MCF-7 human breast cancer cells. The removal of phenol red, the pH indicator in tissue culture medium that is weakly estrogenic (Y. Berthois et al., Proc. Natl. Acad. Sci. USA, 83:2496-2500, 1986), immediately slows the cell proliferation rate, and MCF-7 cells grown in phenol red-free medium with charcoal dextran-treated serum for periods up to 1 mo maintain this reduced rate of cell proliferation. In these short-term phenol red-withdrawn cells, estradiol stimulates proliferation markedly and reproducibly, and antiestrogens inhibit estrogen-stimulated proliferation. Antiestrogens by themselves appear as partial agonists/antagonists; at low concentrations they stimulate proliferation weakly, but they show no stimulation at the high concentrations where they fully inhibit estrogen-stimulated proliferation. In contrast to the short-term phenol red-withdrawn cells, cells maintained for several months (5 to 6 mo) in the apparently complete absence of estrogens (no phenol red, with charcoal dextran-treated calf serum) show a markedly increased basal rate of cell proliferation; estradiol is unable to increase this rate of proliferation further, but antiestrogens are able to decrease proliferation. This change in growth pattern is associated with a 3-fold increase in cellular estrogen receptor levels. Despite their differing basal growth rates, cells grown in either the short-term (less than 1 mo) or long-term (greater than 6 mo) absence of estrogens both have progesterone receptor levels that are very low and, in both cases, estradiol increases progesterone receptor levels markedly. Thus, under long-term estrogen-free conditions, there is a dissociation between the stimulation of cell proliferation and of specific protein synthesis (progesterone receptor) by estrogen. The increase in the cell proliferation rate observed in cells grown in the long-term absence of estrogen may reflect altered regulation of growth factor production or altered sensitivity to growth factors in the medium or produced by the cells themselves. Hence, these breast cancer cells adapt significantly to long-term growth in estrogen-free conditions, an observation that may be relevant to understanding the growth of hormone-responsive human breast cancers in vivo.

An evaluation of the involvement of polyamines in modulating MCF-7 human breast cancer cell proliferation and progesterone receptor levels by estrogen and antiestrogen.

The present studies were undertaken to determine the importance of the polyamine biosynthetic pathway in cellular proliferation and hormone-regulated progesterone receptor synthesis in estrogen receptor-containing breast cancer cells. Treatment of MCF-7 cells with difluoromethylornithine (DFMO), the irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), prevented estradiol-induced cell proliferation in a dose-dependent fashion. DFMO inhibition of estradiol-induced cell proliferation was completely recoverable by the addition of exogenous putrescine while putrescine alone did not stimulate proliferation of control cells. ODC activity was 4-fold greater in estrogen-treated cells and DFMO (5 mM) fully inhibited ODC activity. DFMO was able to suppress only slightly further the proliferation of antiestrogen (tamoxifen) treated cells and putrescine was able to recover this DFMO inhibition. In contrast to the suppressive effect of DFMO on cell proliferation, DFMO had no effect on the ability of estrogen to stimulate increased (4-fold elevated) levels of progesterone receptor. Hence, while ODC activity appears important for estrogen-induced cell proliferation, inhibition of the activity of this enzyme has no effect on the ability of estradiol to increase cellular progesterone receptor content.

Evolution of chick type I procollagen genes.

Although the major types of vertebrate collagen have a number of structural properties in common, significant DNA sequence homologies have not been detected between different portions of the helical coding domains within the same gene or between different genes. However, under non-stringen hybridization conditions we found considerable cross-homology within and between alpha 1(I) and alpha 2(I) chick cDNAs in the coding regions for helical sequences. Detailed analyses at the DNA sequence level have led us to propose that the gene for chick pro alpha 2(I) collagen arose from a 9-bp primordial sequence. A consensus sequence for the 9-bp repeat was derived: GGTCCTCCT, which codes for a Gly-Pro-Pro triplet. The primordial ancestor of this 9-bp unit, GGTCCTXCT, apparently underwent duplication and divergence. Each resulting 9-bp sequence was triplicated to form a 27-bp domain, and a condensation event produced a 54-bp domain. This genetic unit then underwent multiple rounds of amplification to form the ancestral gene for the full-length helical section of alpha 2(I). A different 9-bp consensus sequence (GGTCCCCCC) seems to have been the basis of the chick pro alpha 1(I) gene.

Relationships among uterine growth, ornithine decarboxylase activity and polyamine levels: studies with estradiol and antiestrogens.

We have examined the effects of estradiol (E2) and antiestrogen (AE) on ornithine decarboxylase (ODC) activity and uterine polyamine concentrations as an aid to understanding the dissimilar effects of E2 and AE on uterine growth. ODC activity rises rapidly from very low levels in immature (day 20-23) rat uteri, showing two markedly (approximately 500-fold) increased peaks of activity at 5 h and 16 h after E2 (2 micrograms) injection. After AE (50 micrograms CI628 or U23469) treatment, the temporal increase in ODC activity is slow and only one major peak is found at 24 h. Daily injections of E2 over a 3-day period evoke continued stimulation of uterine ODC activity; however, the same daily treatment regimen with AE results in stimulation of ODC activity only during the first day. After pretreatment with AE, E2 can still elicit the early (5 h) peak of ODC activity, but the later (16 h) peak of ODC activity is blocked. Quantitation of uterine polyamines by high performance liquid chromatography reveals a 1.5-2-fold increase in the concentration of spermidine after 1 day of E2 or AE exposure, with little change in putrescine or spermine levels. After 3 days of E2, AE, or E2 plus AE treatment, spermidine concentrations are elevated 2-2.5-fold and spermine concentrations are elevated 1.5-fold. Putrescine concentrations are unchanged. Hence, regardless of the different degree to which the uterus is stimulated to grow in response to E2 and/or AE, there are corresponding changes in uterine ODC activity, such that polyamine concentrations are elevated to a similar extent in the E2- or AE-treated uterus.