From T cell “exhaustion” to anti-cancer immunity

The immune system has the potential to protect from malignant diseases for extended periods of time. Unfortunately, spontaneous immune responses are often inefficient. Significant effort is required to develop reliable, broadly applicable immunotherapies for cancer patients. A major innovation was transplantation with hematopoietic stem cells from genetically distinct donors for patients with hematologic malignancies. In this setting, donor T cells induce long-term remission by keeping cancer cells in check through powerful allogeneic graft-versus-leukemia effects. More recently, a long awaited breakthrough for patients with solid tissue cancers was achieved, by means of therapeutic blockade of T cell inhibitory receptors. In untreated cancer patients, T cells are dysfunctional and remain in a state of T cell "exhaustion". Nonetheless, they often retain a high potential for successful defense against cancer, indicating that many T cells are not entirely and irreversibly exhausted but can be mobilized to become highly functional. Novel antibody therapies that block inhibitory receptors can lead to strong activation of anti-tumor T cells, mediating clinically significant anti-cancer immunity for many years. Here we review these new treatments and the current knowledge on tumor antigen-specific T cells.

Using computational fluid dynamics to predict head losses in the auxiliary elements of a microirrigation sand filter

It is often assumed that total head losses in a sand filter are solely due to the filtration media and that there are analytical solutions, such as the Ergun equation, to compute them. However, total head losses are also due to auxiliary elements (inlet and outlet pipes and filter nozzles), which produce undesirable head losses because they increase energy requirements without contributing to the filtration process. In this study, ANSYS Fluent version 6.3, a commercial computational fluid dynamics (CFD) software program, was used to compute head losses in different parts of a sand filter. Six different numerical filter models of varying complexities were used to understand the hydraulic behavior of the several filter elements and their importance in total head losses. The simulation results show that 84.6% of these were caused by the sand bed and 15.4% were due to auxiliary elements (4.4% in the outlet and inlet pipes, and 11.0% in the perforated plate and nozzles). Simulation results with different models show the important role of the nozzles in the hydraulic behavior of the sand filter. The relationship between the passing area through the nozzles and the passing area through the perforated plate is an important design parameter for the reduction of total head losses. A reduced relationship caused by nozzle clogging would disproportionately increase the total head losses in the sand filter

Os DNA sintéticos anti-sentido

One old dream of the chemist in the field of the drug research is to create molecules capable of reaching their target with the precision of a missile. To accomplish it these molecules must have the propriety of distinguishing qualitative differences between healthy and diseased cells. A therapy based on this principle, able of eradicating specifically defective cells, or cells affected by a pathogen has an enormous advantage with the regard to the classical approach in which the cytotoxic drugs merely exploit quantitative biochemical and kinetic differences between abnormal and normal cells. We present in this article a review on the chemical synthesis of analogues of desoxyribonucleotides and on results obtained on the specific and irreversible inhibition of undesired genetic expression using the antisense principle.

Effects of Cytochrome P450 Enzyme Inhibitors on the Pharmacokinetics of Nonsteroidal Anti-inflammatory Drugs and Venlafaxine

Cytochrome P450 (CYP) enzymes play a pivotal role in the metabolism of many drugs. Inhibition of CYP enzymes usually increases the plasma concentrations of their substrate drugs and can thus alter the safety and efficacy of these drugs. The metabolism of many widely used nonsteroidal antiinflammatory drugs (NSAIDs) as well as the metabolism of the antidepressant venlafaxine is nown to be catalyzed by CYP enzymes. In the present studies, the effect of CYP inhibition on the armacokinetics and pharmacodynamics of NSAIDs and venlafaxine was studied in clinical trials with healthy volunteers and with a crossover design, by using different antifungal agents as CYP inhibitors. The results of these studies demonstrate that the inhibition of CYP enzymes leads to increased concentrations of NSAIDs. In most cases, the exposure to ibuprofen, diclofenac, etoricoxib, and meloxicam was increased 1.5to 2 fold when they were used concomitantly with antifungal agents. CYP2D6 inhibitor, terbinafine, substantially increased the concentration of parent venlafaxine, whereas the concentration of active moiety of venlafaxine (parent drug plus active metabolite) was only slightly increased. Voriconazole, an inhibitor of the minor metabolic pathway of venlafaxine, produced only minor changes in the pharmacokinetics of venlafaxine. These studies show that an evident increase in the concentrations of NSAIDs may be expected, if they are used concomitantly with CYP inhibitors. However, as NSAIDs are generally well tolerated, use of single doses of NSAIDs concomitantly with CYP inhibitors is not likely to adversely affect patient safety, whereas clinical relevance of longterm concomitant use of NSAIDs with CYP inhibitors needs further investigation. CYP2D6 inhibitors considerably affect the pharmacokinetics of venlafaxine, but the clinical significance of this interaction remains unclear.

Síntese do anti-helmíntico praziquantel,a partir da glicina

This paper deals mainly with the synthesis of praziquantel, a powerful anti-helminthic used against schistosomiasis, an endemic disease which infest millions of people around the world.

Convergent Approaches for the Synthesis of the Anti-tumoral Peptide, Kahalalide F. Study of Orthogonal Protecting Groups

Kahalalide compounds are peptides that are isolated from a Hawaiian herbivorous marine species of mollusc, Elysia rufescens, and its diet, the green alga Bryopsis sp. Kahalalide F and its synthetic analogues are the most promising compounds of the Kahalalide family because they show anti-tumoral activity. Linear solid-phase syntheses of Kahalalide F have been reported. Here we describe several new improved synthetic routes based on convergent approaches with distinct orthogonal protection schemes for the preparation of Kahaladide analogues. These strategies allow a better control and characterization of the intermediates because more reactions are performed in solution. Five derivatives of Kahalalide F were synthesized using several convergent approaches.

A utilização do safrol, principal componente químico do óleo de sassafráz, na síntese de substâncias bioativas na cascata do ácido araquidônico: antiinflamatórios, analgésicos e anti-trombóticos

In this paper we describe the results of a research effort developed in Laboratório de Avaliação e Síntese de Substancias Bioativas (LASSBio, UFRJ) in the utilization of Brazilian abundant natural product, safrole (1), the principal chemical constituent of Sassafras oil (Ocotea pretiosa), as an attractive synthon to access different chemical class of bioactive compounds, as prostaglandins analogues, non-steroidal antiinflammatory agents and antithrombotic compounds.

A química medicinal de N-acilidrazonas: novos compostos-protótipos de fármacos analgésicos, antiinflamatórios e anti-trombóticos

In this article are described new bioactive N-acylhydrazone (NAH) derivatives, structurally designed as optimization of aryl hydrazones precursors planned by molecular hybridization of two 5-lipoxigenase inhibitors, e.g. CBS-1108 and BW-755c. The analgesic, antiedematogenic and anti-platelet aggregating profile of several isosteric compounds was investigated by using classic pharmacological assays in vivo and ex-vivo, allowing to identify new potent peripheric analgesic lead, a new anti-inflammatory and an antithrombotic agent. During this study was discovered dozen of active NAH compounds clarifying the structure-activity relationship for this series of NAH derivatives, indicating the pharmacophore character of the N-acylhydrazone functionality.

Estratégias farmacológicas para a terapia anti-AIDS

The replicative cycle of HIV presents several events. The proteins involved in these events can be anticipated as pharmacological targets, aiming to the development of anti viral agents. Presently, there are fifteen commercially available anti-HIV drugs, which act at substrate binding site of reverse transcriptase (zidovudine, didanosine, zalcitabine, stavudine, lamivudine and abacavir), at a non-substrate binding site of reverse transcriptase (nevirapine, delavirdine and efavirenz), or by inhibiting HIV protease activity (saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir). The present review focus both on these established classes of drugs and on new classes of compounds acting on other virus specific steps.

Development of a Filter Aid Proportioning, Mixing, and Feeding System for a Polishing Filter

The purpose of this work was to study the characteristics of the most commonly used filter aid materials and their influences on the design of proportioning, mixing, and feeding system for polishing filter family. Based on the literature survey and hands-on experience a system was designed with defined equipment and capital and operating costs. The system was designed to serve precoating and bodyfeeding applications and is easily extended to be used in multiple filter processes. Also a test procedure was carried out where influences of flux and filter cloths to accumulated cake were studied. Filter aid is needed in challenging conditions to improve filtration efficiency and cleaning, and thus extend the operating life of the filter media. Filter aid preparation and feeding system was designed for the use of two different filter aids; precoat and bodyfeed. Precoating is used before the filtration step initiates. If the solids in the filterable solution have a tendency to clog the filter bag easily, precoat is used on the filter bag to obtain better filtration efficiency and quality. Diatomite or perlite is usually used as a precoating substance. The intention is to create a uniform cake to the overall surface of the filter cloth, with predetermined thickness, 2 – 5 mm. This ensures that the clogging of the filter cloth is reduced and the filtration efficiency is increased. Bodyfeed is used if the solids in the filterable solution have a tendency to form a sticky impermeable filter cake. The cake properties are enhanced by maintaining the permeability of the accumulating cake by using the filter aid substance as bodyfeed during the filtration process.

Cleaning of ceramic filter plates

In this thesis, cleaning of ceramic filter plates clogged by iron oxides was studied. Oxalic acid is considered as the most effective cleaning agent for the plates fouled by iron oxides, but when using oxalic acid, sparingly soluble calcium oxalate may be formed and it can blind the filter media. Suitability of another chemical for cleaning the plates clogged by iron oxides was studied in this thesis. The literature part was mostly about the properties of the chemical, about its reactions, industrial uses, safety issues etc. In the experimental part, the efficiency of the chemical for cleaning of the ceramic plates clogged by iron oxides was studied. Two kinds of plates were used in the experiments; the others were clogged by hematite and the others by magnetite. Both soaking and flow-through experiments were done. A suitable concentration, pH and temperature were tried to find in the experiments. Also the effect of ultrasound was studied. The efficiency of the cleaning was examined by measuring the permeability of the plates during the experiments. ICP-OES analysis was performed for determining the amount of dissolved iron in the washing solution. Some experiments were also done with oxalic acid. The results from the oxalic acid experiments were compared to the results from the experiments with the other chemical. In the experiments with the other chemical, the permeability increased more and the amounts of dissolved iron were larger. According to the results from the experiments, the method of application of the washing solutions had an impact on the washing results.

Drogas anti-VIH: passado, presente e perspectivas futuras

Currently available anti-HIV drugs can be classified into three categories: nucleoside analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). In addition to the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (1) viral adsorption, through binding to the viral envelope glycoprotein gp120; (2) viral entry, through blockage of the viral coreceptors CXCR4 and CCR5; (3) virus-cell fusion, through binding to the viral envelope glycoprotein gp 41; (4) viral assembly and disassembly through NCp7 zinc finger-targeted agents; (5) proviral DNA integration, through integrase inhibitors and (6) viral mRNA transcription, through inhibitors of the transcription (transactivation) process. Also, various new NRTIs, NNRTIs and PIs have been developed, possessing different improved characteristics.