Comparison of a daily and alternate-day photobiomodulation protocol in the prevention of oral mucositis in patients undergoing radiochemotherapy for oral cancer: a triple-blind, controlled clinical trial.

BACKGROUND: Preventive Photobiomodulation Therapy (PBMT) significantly reduces oral mucositis (OM) severity in patients undergoing Radiochemotherapy (RCT) for the treatment of oral cancer, but daily applications generate cost, overload the dental team, and reduce the number of patients assisted.To evaluate the effectiveness of two PBMT protocols in preventing OM in patients undergoing RCT for oral cancer. MATERIAL AND METHODS: 16 patients diagnosed with oral cancer undergoing RCT were included, equally divided into two groups: a group treated daily with PBMT, and another group also submitted to daily treatment, however, performing the application of PBMT every three days, interspersed with a simulation of PBMT (placebo). A red laser was used (~660 nm), 0.1W power, 1J of energy applied per point, 9 points per area (labial mucosa, buccal mucosa, lateral borders of the tongue, body of the tongue, and floor of the mouth) from the beginning of RCT until the end of the oncological treatment. Daily assessments were performed regarding OM scores, the World Health Organization (WHO) pain scale, and the visual analog scale (VAS). Weight, salivary flow (SGAPP), OHIP-14, and DMFT were evaluated on the initial and final days of RT. OM incidence and clinical data were compared by Pearson's chi-square test or Fisher's exact test. Pain and other scale scores were compared using the Mann-Whitney and Friedman/Dunn tests (SPSS v20.0 p<0.05). RESULTS: In the group with PBMT on alternate days, there was an increase in the frequency of grade 2 and grade 3 oral mucositis and an increased risk of grade 2 oral mucositis, in addition to higher mean pain scores and greater reduction in salivary flow. CONCLUSIONS: The daily PBMT protocol proved more effective in controlling the frequency and severity of OM, pain, and salivary flow.

Interleukin-4 variant (BAY 36-1677) selectively induces apoptosis in acute lymphoblastic leukemia cells.

Interleukin 4 (IL-4) suppresses the growth of acute lymphoblastic leukemia (ALL) cells, but its clinical usefulness is limited by proinflammatory activity due mainly to the interaction of cytokine with endothelial cells and fibroblasts. Stroma-supported cultures of leukemic lymphoblasts were used to test the antileukemic activity of an IL-4 variant, BAY 36-1677, in which the mutations Arg 121 to Glu and Thr 13 to Asp ensure high affinity for IL-4Ralpha/IL-2Rgamma receptors expressed by lymphoid cells, without activation of the IL-4Ralpha/IL-13Ralpha receptors mainly expressed by other cells. BAY 36-1677 (25 ng/mL) was cytotoxic in 14 of 16 cases of B-lineage ALL; the median reduction in cell recovery after 7 days of culture was 85% (range, 17%-95%) compared to results of parallel cultures not exposed to the cytokine. Twelve of the 14 sensitive cases had t(9;22) or 11q23 abnormalities; 3 were obtained at relapse. BAY 36-1677 induced apoptosis in leukemic lymphoblasts but did not substantially affect the growth of normal CD34+ cells, thus conferring a growth advantage to normal hematopoietic cells over leukemic lymphoblasts in vitro. BAY 36-1677 had antileukemic activity equal or superior to that produced by native IL-4, but it lacked any effects on the growth of endothelial cells and fibroblasts. The molecular manipulation of IL-4 to abrogate its proinflammatory activity has generated a novel and therapeutically promising cytokine for the treatment of high-risk ALL.

A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo.

Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with approximately 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees, and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.

An immune cell-selective interleukin 4 agonist.

Interleukin 4 (IL-4) is a pleiotropic cytokine. Of the cell types responsive to IL-4, T cells express one IL-4 receptor (IL-4R) type, IL-4Ralpha/IL-2Rgamma (class I IL-4R), whereas endothelial cells express another type, IL-4Ralpha/IL-13Ralpha (class II IL-4R). It was hypothesized that IL-4 variants could be generated that would be selective for cell types expressing the different IL-4Rs. A series of IL-4 muteins were generated that were substituted in the region of IL-4 implicated in interactions with IL-2Rgamma. These muteins were evaluated in T cell and endothelial cell assays. One of these muteins, containing the mutation Arg-121 to Glu (IL-4/R121E), exhibited complete biological selectivity for T cells, B cells, and monocytes, but showed no activity on endothelial cells. Receptor binding studies indicated that IL-4/R121E retained physical interaction with IL-2Rgamma but not IL-13Ralpha; consistent with this observation, IL-4/R121E was an antagonist of IL-4-induced activity on endothelial cells. IL-4/R121E exhibits a spectrum of activities in vitro that suggest utility in the treatment of certain autoimmune diseases.

Mechanisms of receptor-mediated rhinovirus neutralization defined by two soluble forms of ICAM-1.

The majority of human rhinoviruses use intercellular adhesion molecule 1 (ICAM-1) as a cell surface receptor. Two soluble forms of ICAM-1, one corresponding to the entire extracellular portion [tICAM(453)] and one corresponding to the two N-terminal immunoglobulin-like domains [tICAM(185)], have been produced, and their effects on virus-receptor binding, virus infectivity, and virus integrity have been examined. Results from competitive binding experiments indicate that the virus binding site is largely contained within the two N-terminal domains of ICAM-1. Virus infectivity studies indicate that tICAM(185) prevents infection by direct competition for receptor binding sites on virus, while tICAM(453) prevents infection at concentrations 10-fold lower than that needed to inhibit binding and apparently acts at the entry or uncoating steps. Neutralization by both forms of soluble ICAM-1 requires continual presence of ICAM-1 during the infection and is largely reversible. Both forms of soluble ICAM-1 can alter rhinovirus to yield subviral noninfectious particles lacking the viral subunit VP4 and the RNA genome, thus mimicking virus uncoating in vivo, although this irreversible modification of rhinovirus is not the major mechanism of virus neutralization.

The major human rhinovirus receptor is ICAM-1.

The major human rhinovirus receptor has been identified with monoclonal antibodies that inhibit rhinovirus infection. These monoclonal antibodies recognize a 95 kd cell surface glycoprotein on human cells and on mouse transfectants expressing a rhinovirus binding phenotype. Purified 95 kd protein binds to rhinovirus in vitro. Protein sequence from the 95 kd protein showed an identity with that of intercellular adhesion molecule-1 (ICAM-1); a cDNA clone obtained from mouse transfectants expressing the rhinovirus receptor had essentially the same sequence as ICAM-1. Thus, the major human rhinovirus receptor is ICAM-1. The gene for this receptor maps to human chromosome 19, which also contains the genes for a number of other picornavirus receptors.

Model for mammalian metallothionein structure.

The results of physicochemical studies of mammalian metallothioneins are summarized and used to propose a model of the protein. The primary structures of all mammalian metallothioneins are very homologous; there are 38 invariant residues and 20 of them are cysteines. The results of UV and CD optical studies indicated that all 20 cysteines are involved in the ligation of 7 mol of metal per mol of metallothionein and that the protein does not contain any alpha-helix structure. A theoretical analysis by the Chou-Fasman method has predicted 11 beta-bends, each one involving at least one cysteine residue. The most significant structural data, provided by 113Cd NMR, demonstrated that the 7 mol of bound Cd2+ are arranged in two separate metal clusters, one containing four metal ions and the other containing three, with all Cd2+ tetrahedrally coordinated to cysteine thiolate ligands. The 11 cysteine residues of the carboxyl-terminal portion of the metallothionein chain (residues 30-61) are ligated to the 4-metal cluster as shown by 113Cd NMR of this enzymatically cleaved fragment. The remaining cysteine residues from the amino-terminal polypeptide portion (residues 1-29) form the 3-metal cluster. Such a division of the chain is consistent with the presence of an intron in the mouse metallothionein-1 gene corresponding to residue 32 in the polypeptide chain. A two-domain molecular model has been constructed based on an analysis of all the available data and is described in detail. The accuracy of this model was tested by 1H NMR at 500 MHz and the data are in agreement with our proposed structure.