In Vitro Contraction of the Canine Corpus Cavernosum Penis by Direct Perfusion with Prolactin or Growth Hormone

Purpose

It is well established that hyperprolactinemia, most typically seen in prolactinoma patients, causes hypogonadism and impotence. There seem to be a good possibility that hyperprolactinemia causes impotence, at least partially via some intrinsic property of prolactin (PRL), rather than through its suppressive effects on the hypothalamic-pituitary-gonadal testosterone dynamics. In the present investigation, we used an in vitro canine model to attempt to clarify whether direct action of PRL on the corpus cavernosum penis may lead to erectile insufficiency. Growth hormone (GH) and placental lactogen (PL), both having close structural and functional homologies to PRL, were also studied.

Materials and Methods

Isometric tension measurement with cavernous strips was performed in the presence or absence of 10 sup -5 to 10 sup -9 M. PRL, GH, or PL in the perfusion medium. The tension change induced by the test substances was normalized relative to that induced by 120 mEq KCl.

Results

Both PRL and GH produced dose-related elevations (p less than 0.01) of the cavernous tension, whereas PL and thiol-cleaved PRL in comparable doses were without effect (p greater than 0.05). When the tension rise produced by 120 mEq KCl was taken as 100 percent, the maximum contractions produced by PRL and GH were 80 percent and 110 percent. The minimum effective concentration was 10 sup -8 to 10 sup -7 M. for both PRL and GH. Pretreatment with indomethacin (10 sup -5 M.), but not tetrodotoxin (10 sup -5 M.), partially suppressed (p less than 0.05) the effects of PRL.

Conclusion

These results suggest that PRL and GH directly and specifically produced contraction of the corpus cavernosum penis, resulting in erectile insufficiency, and that the effect of PRL is partially mediated by prostaglandin.     

Mutagenicity of N-butyl-N-(4-hydroxybutyl)nitrosamine, a bladder carcinogen, and related compounds.

N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN), which specifically induces bladder tumors, was shown to be mutagenic to Salmonella typhimurium strains TA 1535 and TA100 in the presence of an S-9 mix prepared from the liver of rats treated with polychlorinated biphenyl. Reduced nicotinamide adenine dinucleotide was a more effective cofactor than reduced nicotinamide adenine dinucleotide phosphate in the activation of BBN by the rat liver S-9 fraction, N-Butyl-N-(3-carboxypropyl)nitrosamine, reported to be the main urinary metabolite of BBN as well as of N,N-dibutylnitrosamine and to induce urinary bladder tumors specifically, was found to be mutagenic without metabolic activation by the S-9 mix. The mutagenicities of 31 compounds related structurally or metabolically to BBN and N,N-dibutylnitrosamine were tested. Of these compounds, 13 have previously been demonstrated to be carcinogenic, and nine have been shown to be noncarcinogenic. All the carcinogenic compounds were found to be mutagenic to strain TA1535 with or without the S-9 mix. Four of the nine noncarcinogenic compounds were also mutagenic. These "false-positive" compounds were predicted, in fact, to be carcinogenic.     

Balloon-assisted coil placement in wide-necked cerebral aneurysms: preliminary clinical experience

Endovascular treatment of wide-necked cerebral aneurysms with Guglielmi detachable coils (GDCs) has been limited due to coil protrusion into the artery. Seven patients with wide-necked cerebral aneurysms were treated with GDCs with temporary balloon inflation for mechanical protection during coil placement. Transarterial embolization of the aneurysm with GDCs had failed due to coil protrusion into the parent artery. The use of simultaneous temporary balloon protection achieved more dense intra-aneurysmal coil packing, especially in the neck, without compromising the parent artery.     

Epidermal growth factor receptor tyrosine kinase inhibitor does not improve paclitaxel effect in an orthotopic mouse model of lung cancer.

PURPOSE: The purpose is to evaluate whether inhibition of epidermal growth factor receptor (EGFR) activation by PKI166, an EGFR-tyrosine kinase inhibitor, affects growth of human lung cancer implanted orthotopically into the lungs of nude mice. EXPERIMENTAL DESIGN: Lungs of mice were injected with NCI-H358 human bronchioloalveolar cancer cells. In three experiments, groups of mice (n = 10 per group) were randomized 7 days after tumor implantation to receive one of the following treatments: i.p. paclitaxel 100 or 200 microg (4 or 8 mg/kg) once per week, oral PKI166 100 or 200 mg/kg three times per week, paclitaxel plus PKI166, or i.p. saline and oral PKI166-vehicle (control) for 5 weeks. Mice were killed 6.5 to 8 weeks after tumor implantation. The experiments were repeated with PC14PE6 human lung adenocarcinoma cells to assess effect on survival. RESULTS: Immunohistochemical analyses revealed the expression and phosphorylation of EGFR in the growing tumors. Treatment with PKI166 alone or in combination with paclitaxel diminished activation of EGFR on tumor cells, yet maximal therapeutic effect was observed in mice treated with paclitaxel alone. Activated mitogen-activated protein kinase and basic fibroblast growth factor expression were similar in all treatment groups. Survival in mice treated with the combination of paclitaxel and PKI166 was shorter than in those treated with paclitaxel alone. CONCLUSIONS: Our results suggest that concurrent administration of EGFR-tyrosine kinase inhibitor and chemotherapy is equivalent and may indeed be inferior to chemotherapy alone, even if EGFR is functional and its phosphorylation effectively inhibited. Our data show that the interaction of EGFR-TKIs and chemotherapy is complex and suggest that other growth factors may activate the downstream signaling events.     

cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway

BACKGROUND.: Cellular proliferation is a key factor in the enlargement of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). We determined the extent to which adenosine 3':5'-cyclic monophosphate (cAMP) may regulate the in vitro proliferation of cyst epithelial cells derived from human ADPKD cysts. METHODS.: Epithelial cells from cysts of individuals with ADPKD and from normal human kidney cortex (HKC) of individuals without ADPKD were cultured. The effects of agonists and inhibitors on the rate of cellular proliferation and the activation of extracellular signal-regulated kinase (ERK1/2) were determined. RESULTS.: 8-Br-cAMP (100 micromol/L) stimulated the proliferation of cells from eight different ADPKD subjects to 99.0% above baseline; proliferation was inhibited by protein kinase A (PKA) antagonists H-89 (97%) and Rp-cAMP (90%). Forskolin (10 micromol/L), which activates adenylyl cyclase, increased proliferation 124%, and receptor-mediated agonists arginine vasopressin, desmopressin, secretin, vasoactive intestinal polypeptide, and prostaglandin E2 stimulated proliferation 54.2, 56.3, 46.7, 37.1, and 48.3%, respectively. The mitogen extracellular kinase (MEK) inhibitor PD98059 completely inhibited ADPKD cell proliferation in response to cAMP agonists, but genistein, a receptor tyrosine kinase inhibitor, did not block cAMP-dependent proliferation. cAMP agonists increased the activity of ERK above control levels within five minutes. In contrast to ADPKD, proliferation and ERK activity of cells derived from normal HKC were not stimulated by cAMP agonists, although electrogenic Cl- secretion was increased by these agonists in both ADPKD and HKC cell monolayers. CONCLUSIONS.: We conclude that cAMP agonists stimulate the proliferation of ADPKD but not HKC epithelial cells through PKA activation of the ERK pathway at a locus distal to receptor tyrosine kinase. We suggest that the adenylyl cyclase signaling pathway may have a unique role in determining the rate of cyst enlargement in ADPKD through its actions to stimulate cellular proliferation and transepithelial solute and fluid secretion.     

Primary Transitional Cell Carcinoma of the Fallopian Tube: A Case Report and Review of the Literature

Primary carcinoma of the fallopian tube is extremely rare and the preoperative diagnosis is often misdiagnosed as an ovarian carcinoma. We report a patient with primary carcinoma of the fallopian tube, strongly suspected preoperatively on the basis of characteristic clinical symptoms, elevated CA125 levels, and transvaginal sonography, computed tomography, and magnetic resonance imaging findings. The histology of fallopian tube carcinoma was demonstrated as transitional cell carcinoma. Extensive review of the literature showed that our case seemed to be the 14th case of primary transitional cell carcinoma of the fallopian tube.     

Sequence Analysis of Genes Encoding Rodent Homologues of the Human Tumor-rejection Antigen SART-1

Human SART-1 ( hSART-1 ) gene encodes a 125 kD protein with a leucine-zipper motif expressed in the nucleus of all proliferating cells, and a 43 kD protein expressed in the cytosol of most epithelial cancers. In this study, two rodent genes ( rSART-1 and mSART-1 ) homologous to hSART-1 were cloned from cDNA libraries of murine brain and a rat tumor cell line, respectively. mSART-1 and rSART-1 were highly homologous to hSART-1 with 86% and 84% identity at the nucleotide level, and 95% and 91% at the protein level, respectively. The leucine zipper domain and two basic amino acid portions that bind DNA, as well as peptide sequences recognized by human cyto-toxic T lymphocytes (CTLs), were all conserved in these rodent genes. Nuclear protein homologous to the 125 kD hSART-1₈₀₀ protein, but not to the 43 kD cytosol SART-1₂₅₉ protein, was detectable with specific antibody in the nuclear fractions of rodent tumor cell lines, and normal rodent fetal liver and testis. These rodent genes should be a novel tool for studies on the biological roles of the SART-1 gene, and also in the construction of animal models of specific immuno-therapy using SART-1 gene products.