Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity

Transforming growth factor beta (TGF-beta), a pleiotropic cytokine that regulates cell growth and differentiation, is secreted by many human tumors and markedly inhibits tumor-specific cellular immunity. Tumors can avoid the differentiating and apoptotic effects of TGF-beta by expressing a nonfunctional TGF-beta receptor. We have determined whether this immune evasion strategy can be manipulated to shield tumor-specific cytotoxic T lymphocytes (CTLs) from the inhibitory effects of tumor-derived TGF-beta. As our model we used Epstein-Barr virus (EBV)-specific CTLs that are infused as treatment for EBV-positive Hodgkin disease but that are vulnerable to the TGF-beta produced by this tumor. CTLs were transduced with a retrovirus vector expressing the dominant-negative TGF-beta type II receptor HATGF-betaRII-Deltacyt. HATGF-betaRII-Deltacyt- but not green fluorescence protein (eGFP)-transduced CTLs was resistant to the antiproliferative and anticytotoxic effects of exogenous TGF-beta. Additionally, receptor-transduced cells continued to secrete cytokines in response to antigenic stimulation. TGF-beta receptor ligation results in phosphorylation of Smad2, and this pathway was disrupted in HATGF-betaRII-Deltacyt-transduced CTLs, confirming blockade of the signal transduction pathway. Long-term expression of TGF-betaRII-Deltacyt did not affect CTL function, phenotype, or growth characteristics. Tumor-specific CTLs expressing HATGF-betaRII-Deltacyt should have a selective functional and survival advantage over unmodified CTLs in the presence of TGF-beta-secreting tumors and may be of value in treatment of these diseases.     

Effect of nitric oxide modulation on systemic haemodynamics and platelet activation determined by P-selectin expression

Inhibiting platelet and endothelial nitric oxide production favours platelet adhesion and aggregation, and arterial vasoconstriction. This study investigated the effect of NG-nitro-l-arginine methyl ester (L-NAME), a stereospecific inhibitor of nitric oxide synthesis, on P-selectin expression on platelets, platelet-derived microparticles and platelet-leucocyte aggregates, and on soluble P-selectin levels. Twelve healthy male volunteers were infused intravenously with L-NAME and then with a 10% solution of either l- or d-arginine. Blood pressure responses were recorded and whole blood and serum collected at baseline and after each infusion. P-selectin expression was analysed in all samples by flow cytometry. Serum levels of soluble P-selectin were batch analysed using an enzyme-linked immunosorbent assay at the end of the study. P-selectin expression on platelets, platelet-derived microparticles and platelet-leucocyte aggregates did not vary significantly from baseline levels following the infusion of L-NAME or l- or d-arginine. However, endothelial nitric oxide synthase inhibition caused a marked elevation of arterial blood pressure (P < 0.01) that was restored to pretreatment values by l- but not d-arginine. Serum levels of the soluble form decreased significantly (P = 0.001) following the infusion of l- and d-arginine compared with samples taken at baseline and following L-NAME infusion. In conclusion, inhibition of constitutive nitric oxide synthase in the endothelium and platelets produced significant increases in blood pressure but did not alter platelet membrane expression of P-selectin.     

Gardner P.H. Foley: colorful dean of dental historians

Gardner P. H. Foley, A.B., A.M, D.Sc. (1902-1997) served 41 years as professor of dental literature and history at the Baltimore College of Dental Surgery, Dental School University of Maryland. As "dean of dental historians," Dr. Foley had an illustrious career that spanned 70 years. During his lengthy tenure at Maryland, Foley, who was not a dentist, taught over 3,000 dental students. Foley's Irish background, New England drawl and his early childhood memories and experiences in the charming seaside village, Gloucester, Massachusetts, influenced him throughout his life. Throughout his career, Dr. Foley was motivated to investigate aspects of literature and recorded history pertaining to teeth and dentistry. His extensive research, prodigious memory and numerous published columns, books and articles, have helped establish the important role that dentists have played in historic events throughout the ages. As a founding member of the American Academy of the History of Dentistry, Gardner Foley prepared the first draft of a constitution for the Academy. Dr. Foley left a legacy of accomplishment in the literature and the history of dentistry, which remains a source of pride to all those associated with this profession.     

Gerrit Dou: 17th century Dutch artist portraying dentists at work

The Dutch painter, Gerrit Dou (1613-1675), was, during his lifetime, a prestigious and highly paid artist. Critics and collectors of that era marveled at his extraordinary technical skill, his masterful illusionism and his keen portrayal of everyday life. He was the first artist to perfect the technique of "fine painting"--the production of small, detailed pictures wherein subjects are painted in a photographically realistic style. Because of his exceptional skill in this technique, the brushwork in his painting was almost invisible. Additionally, he masterfully used light and shade to achieve the effect of a third dimension. In many of his portraits, subjects stare ahead from inside a window (or niche), whose sill is overflowing with small, familiar objects. Dou's focus was on 17th century Holland and his work included: portraits, genre (scenes of everyday life) and religious themes. Between 1628 and 1675, he painted about three hundred pictures: six of these portrayed dentists at work. Most artists of those days depicted dentists as plying their trade in theatrical, circus-like environments, as in crowded county fairs. However, Dou's dentists interact with their patients in a realistic, professional manner. In this article, his most famous dental painting, "The Dentist," created in 1672, is analyzed in detail. Over the centuries, Dou's public recognition has faded into obscurity. However, his exceptional talents are currently being rediscovered.