Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against human head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy in which multiple independent lesions develop over time throughout the mucosa of the upper aerodigestive tract. Therefore, the comprehensive treatment of this neoplasm must include a chemopreventive arm to hold premalignant lesions in check, a role well-suited to antiangiogenic agents. Retinoic acid (RA) and interferon alpha (IFN-alpha), drugs with known biological activity against HNSCC when used individually, are also inhibitors of angiogenesis. Here we show that they are remarkably synergistic antiangiogenic agents able to inhibit both the growth and the neovascularization of HNSCC injected into the floor of the mouth of nude mice. The mechanism of action of these drugs as antiangiogenic agents was 2-fold. They decreased the angiogenic activity of the tumor cells, and they caused the endothelial cells to become refractory to inducers of angiogenesis. When tumor cells were treated in vitro with IFN-alpha A/D, there was a dramatic drop in their secretion of interleukin-8, the major angiogenic factor produced by these tumors. When combined with RA, which causes tumor cells to secrete an inhibitor of angiogenesis, there was a synergistic inhibition of both tumor cell growth and secreted angiogenic activity. The combination of RA and IFN-alpha also acted synergistically on endothelial cells by reducing their responsiveness to both interleukin-8 and tumor conditioned media. Doses of each drug could be reduced by two logs without loss of activity. When animals bearing human HNSCC tumor cells were treated systemically with a combination of RA and IFN-alpha A/D at doses that were ineffective when used alone, dramatic decreases in both tumor growth and tumor angiogenesis were seen. These data suggest that the use of antiangiogenic mixtures may be a particularly effective way to design future chemoprevention protocols against HNSCC.     

Inputs to directionally selective simple cells in macaque striate cortex

It is clear that the initial analysis of visual motion takes place in the striate cortex, where directionally selective cells are found that respond to local motion in one direction but not in the opposite direction. Widely accepted motion models postulate as inputs to directional units two or more cells whose spatio-temporal receptive fields (RFs) are approximately 90 degrees out of phase (quadrature) in space and in time. Simple cells in macaque striate cortex differ in their spatial phases, but evidence is lacking for the varying time delays required for two inputs to be in temporal quadrature. We examined the space-time RF structure of cells in macaque striate cortex and found two subpopulations of (nondirectional) simple cells, some that show strongly biphasic temporal responses, and others that are weakly biphasic if at all. The temporal impulse responses of these two classes of cells are very close to 90 degrees apart, with the strongly biphasic cells having a shorter latency than the weakly biphasic cells. A principal component analysis of the spatio-temporal RFs of directionally selective simple cells shows that their RFs could be produced by a linear combination of two components; these two components correspond closely in their respective latencies and biphasic characters to those of strongly biphasic and weakly biphasic nondirectional simple cells, respectively. This finding suggests that the motion system might acquire the requisite temporal quadrature by combining inputs from these two classes of nondirectional cells (or from their respective lateral geniculate inputs, which appear to be from magno and parvo lateral geniculate cells, respectively).     

Role of Epstein-Barr virus in fine-needle aspirates of metastatic neck nodes in the diagnosis of nasopharyngeal carcinoma

The crystal structure of the peptide Boc-Phe-Val-OMe determined by X-ray diffraction methods is reported in this paper. The crystals grown from aqueous methanol are orthorhombic, space group P2(1)2(1)2(1),a = 11.843(2), b = 21.493(4), c = 26.676(4) A3 and V = 6790 A3. Data were collected on a CAD4 diffractometer using MoK alpha radiation (lambda = 0.7107 A) up to Bragg angle theta = 26 degrees. The structure was solved by direct methods and refined by a least-squares procedure to an R value of 6.8% for 3288 observed reflections. There are three crystal-lographically independent peptide molecules in the asymmetric unit. All the three molecules exhibit extended conformation. The sidechain of the Val2 residue shows two different conformations. The conformation of the peptide Boc-Phe-Val-OMe is compared with the conformation of Ac-delta Phe-Val-OH. It is observed that while Boc-Phe-Val-OMe exhibits an extended conformation, Ac-delta Phe-Val-OH shows a folded conformation. The results of this comparison highlight the conformation constraining property of the delta Phe residue. Interestingly, even though Boc-Phe-Val-OMe and Ac-delta Phe-Val-OH are conformationally different, they exhibit similar packing patterns in the solid state.     

Penicillin vs. erythromycin in the treatment of diphtheria

PURPOSE: To review the University of Florida experience in treating ependymomas, analyze prognostic factors, and provide treatment recommendations. METHODS AND MATERIALS: Forty-one patients with ependymoma and no metastases outside the central nervous system received postoperative radiotherapy with curative intent between 1966 and 1989. Ten patients had supratentorial lesions, 22 had infratentorial lesions, and 9 had spinal cord lesions. All patients had surgery (stereotactic biopsy, subtotal resection, or gross total resection). Most patients with high-grade lesions received radiotherapy to the craniospinal axis. Low-grade intracranial lesions received more limited treatment. Spinal cord lesions were treated using either partial spine or whole spine fields. RESULTS: Of 32 intracranial tumors, 21 recurred, all at the primary site; no spinal cord tumors recurred. Overall 10-year survival rates were 51% (absolute) and 46% (relapse-free); by tumor site: spinal cord, 100%; infratentorial, 45%; supratentorial, 20% (p = 0.002). On multivariate analysis, tumor site was the only factor that influenced absolute survival (p = 0.0004); other factors evaluated included grade, gender, age, duration of symptoms, resection extent, primary tumor dose, treatment field extent, surgery-to-radiotherapy interval, and days under radiotherapy treatment. CONCLUSIONS: Patients with supratentorial or infratentorial tumors receive irradiation, regardless of grade. Craniospinal-axis fields are used when spinal seeding is radiographically or pathologically evident. Spinal cord tumors are treated using localized fields to the primary site if not completely resected. Failure to control disease at the primary site remains the main impediment to cure.     

Synthesis and analgesic properties of new 5-thioaryl pyrazole derivatives

A new series 5-thio aryl pyrazole derivatives were proposed aiming analgesic activity. In this work, 8 new compounds of this class were synthesized using usual synthetic methodology, having as key intermediate the 3-methyl-4-nitro-5-chloropyrazole-1-phenyl derivative and subsequent reaction with several nucleophiles sulfides. Pharmacological evaluation of this series showed analgesic activity in the some extent in especially for 5-(4-bromophenyl)-thio-3-methyl-4-nitro-1-phenylpyrazole which was the most potent in this series, presenting an analgesic action comparable to that show by dipyrone.     

Interaction of transport resistances with biochemical reaction in packed-bed solid-state fermentors: effect of temperature gradients

Subdermal superficial liposuction, first presented by the authors at the ISAPS Congress at Zurich in 1989, is performed with thin three-hole Mercedes cannulas (diameter ranges from 1.8 to 2 mm) to treat small and secondary adiposities and to allow better skin retraction. Suction of the subdermal layer of fat reduces the thickness and consistency of the superficial fat and enhances the possibility of skin retraction. In cases where there is a large adiposity of the abdomen, arms, or inner thighs, there is a conspicuous volume of fat whose weight tends to overstretch and to carry the overlying skin downward. In these cases we need to reduce the large fat volume to permit effective skin retraction. Therefore, we apply the principles of traditional liposuction with those of subdermal superficial liposuction to aspirate large amounts of fat from all the adipose layers. We call this technique Massive All Layer Liposuction (MALL). The amount of skin shrinkage after this "defatting" procedure is remarkable and the clinical results are very good. The MALL technique can be applied to other areas as well. In our experience this new liposuction technique has dramatically reduced the indications of abdominoplasties and dermolipectomies of inner thighs and arms.     

Dynamic neural cortical ensembles model

One-layered model of cortical neurons as a set of overlapping ensembles, each with a structure similar to Hopfield network, is proposed. Ensemble equilibrium equation is solved and formulas for connections weights calculation for given set of attractors are obtained. Concept of dynamic attractors that consists of consequent recalling of stored patterns with moving activity through the network is introduced. Role of dynamic attractors in long-term memory is discussed and mechanism for memory recovery after destruction of some neurons is proposed. Results of experiments on associative memory recovery after partial removal of neurons are shown.     

Regulation of periodontal ligament cell functions by interleukin-1beta

Periodontal ligament (PDL) cells maintain the attachment of the tooth to alveolar bone. These cells reside at a site in which they are challenged frequently by bacterial products and proinflammatory cytokines, such as interleukin-1beta (IL-1beta), during infections. In our initial studies we observed that IL-1beta down-regulates the osteoblast-like characteristics of PDL cells in vitro. Therefore, we examined the functional significance of the loss of the PDL cell's osteoblast-like characteristics during inflammation. In this report we show that, during inflammation, IL-1beta can modulate the phenotypic characteristics of PDL cells to a more functionally significant lipopolysaccharide (LPS)-responsive phenotype. In a healthy periodontium PDL cells exhibit an osteoblast-like phenotype and are unresponsive to gram-negative bacterial LPS. Treatment of PDL cells with IL-1beta inhibits the expression of their osteoblast-like characteristics, as assessed by the failure to express transforming growth factor beta1 (TGF-beta1) and proteins associated with mineralization, such as alkaline phosphatase and osteocalcin. As a consequence of this IL-1beta-induced phenotypic change, PDL cells become responsive to LPS and synthesize proinflammatory cytokines. The IL-1beta-induced phenotypic changes in PDL cells were transient, as removal of IL-1beta from PDL cell cultures resulted in reacquisition of their osteoblast-like characteristics and lack of LPS responsiveness. The IL-1beta-induced phenotypic changes occurred at concentrations that are frequently observed in tissue exudates during periodontal inflammation (0.05 to 5 ng/ml). The results suggest that, during inflammation in vivo, IL-1beta may modulate PDL cell functions, allowing PDL cells to participate directly in the disease process by assuming LPS responsiveness at the expense of their normal structural properties and functions.     

The envelope glycoprotein ectodomains determine the efficiency of CD4+ T lymphocyte depletion in simian-human immunodeficiency virus-infected macaques

CD4+ T lymphocyte depletion in human immunodeficiency virus type 1 (HIV-1)-infected humans underlies the development of acquired immune deficiency syndrome. Using a model in which rhesus macaques were infected with chimeric simian-human immunodeficiency viruses (SHIVs), we show that both the level of viremia and the structure of the HIV-1 envelope glycoprotein ectodomains individually contributed to the efficiency with which CD4(+) T lymphocytes were depleted. The envelope glycoproteins of recombinant SHIVs that efficiently caused loss of CD4(+) T lymphocytes exhibited increased chemokine receptor binding and membrane-fusing capacity compared with those of less pathogenic viruses. These studies identify the HIV-1 envelope glycoprotein ectodomains as determinants of CD4(+) T lymphocyte loss in vivo and provide a foundation for studying pathogenic mechanisms.