Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy

BACKGROUND: Flu-like symptoms are common, early transient side effects of paclitaxel chemotherapy. We hypothesized that these symptoms may be due to release of inflammatory cytokines in response to treatment. The objective of this study was to assess changes in plasma levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12, and TNF-alpha during chemotherapy and to correlate these changes with musculoskeletal symptoms. METHODS: Ninety patients with breast cancer were included; 70 patients received single agent paclitaxel either weekly or every 3 weeks and 20 received FAC (5-FU, doxorubicin, cyclophosphamide) chemotherapy. Fifteen healthy volunteers were included as controls. Cytokines and symptoms were measured before starting therapy, on day 3 and on the last day of one treatment cycle. RESULTS: At baseline, all subjects had measurable levels of IL-8 but only 49% had IL-12, 45% had IL-10, 32% had IL-6, and 21% had IL-1beta or TNF-alpha in their plasma. There was no difference in baseline cytokine levels between cancer patients and the healthy volunteers. Schedule-dependent transient changes in the levels of 3 cytokines were observed in the paclitaxel treated patients. In the every 3-week paclitaxel group, IL-6 and IL-8 increased whereas in the weekly paclitaxel group IL-10 increased significantly compared to baseline. Fatigue and flu-like symptoms were also worse on day 3. In the weekly paclitaxel group, increase in IL-10 level correlated positively with joint pain (p=0.003). In the every 3-week paclitaxel group, increase in IL-8 level correlated positively with flu-like symptom (p=0.008). In the FAC-treated group and among the healthy volunteers none of these cytokines increased significantly. CONCLUSIONS: Weekly paclitaxel induces transient increase in IL-10 levels whereas every 3-week higher dose treatments induce IL-8 and IL-6 in the plasma. These changes correlate with joint pain and flu-like symptoms.     

Identification of a subset of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strains able to exploit an alternative coreceptor on untransformed human brain and lymphoid cells

The chemokine receptors CCR5 and CXCR4 are the major coreceptors for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). At least 12 other chemokine receptors or close relatives support infection by particular HIV and SIV strains on CD4(+) transformed indicator cell lines in vitro. However, the role of these alternative coreceptors in vivo is presently thought to be insignificant. Infection of cell lines expressing high levels of recombinant CD4 and coreceptors thus does not provide a true indication of coreceptor use in vivo. We therefore tested primary untransformed cell cultures that lack CCR5 and CXCR4, including astrocytes and brain microvascular endothelial cells (BMVECs), for naturally expressed alternative coreceptors functional for HIV and SIV infection. An adenovirus vector (Ad-CD4) was used to express CD4 in CD4(-) astrocytes and thus confer efficient infection if a functional coreceptor is present. Using a large panel of viruses with well-defined coreceptor usage, we identified a subset of HIV and SIV strains able to infect two astrocyte cultures derived from adult brain tissue. Astrocyte infection was partially inhibited by several chemokines, indicating a role for the chemokine receptor family in the observed infection. BMVECs were weakly positive for CD4 but negative for CCR5 and CXCR4 and were susceptible to infection by the same subset of isolates that infected astrocytes. BMVEC infection was efficiently inhibited by the chemokine vMIP-I, implicating one of its receptors as an alternative coreceptor for HIV and SIV infection. Furthermore, we tested whether the HIV type 1 and type 2 strains identified were able to infect peripheral blood mononuclear cells (PBMCs) via an alternative coreceptor. Several strains replicated in Delta32/Delta32 CCR5 PBMCs with CXCR4 blocked by AMD3100. This AMD3100-resistant replication was also sensitive to vMIP-I inhibition. The nature and potential role of this alternative coreceptor(s) in HIV infection in vivo is discussed.     

Do orthologous gene phylogenies really support tree-thinking?

Background  

Since Darwin's Origin of Species, reconstructing the Tree of Life has been a goal of evolutionists, and tree-thinking has become a major concept of evolutionary biology. Practically, building the Tree of Life has proven to be tedious. Too few morphological characters are useful for conducting conclusive phylogenetic analyses at the highest taxonomic level. Consequently, molecular sequences (genes, proteins, and genomes) likely constitute the only useful characters for constructing a phylogeny of all life. For this reason, tree-makers expect a lot from gene comparisons. The simultaneous study of the largest number of molecular markers possible is sometimes considered to be one of the best solutions in reconstructing the genealogy of organisms. This conclusion is a direct consequence of tree-thinking: if gene inheritance conforms to a tree-like model of evolution, sampling more of these molecules will provide enough phylogenetic signal to build the Tree of Life. The selection of congruent markers is thus a fundamental step in simultaneous analysis of many genes.     

THE RESERVOIR CYTOSKELETON AND A POSSIBLE CYTOSTOMAL HOMOLOGUE IN COLACIUM (EUGLENOPHYCEAE)1

The reservoir cytoskeleton of Colacium Ehrenberg is formed of three bands of microtubules. The microtubules of the dorsal band (DMT) become doublets and are continuous with the longitudinal microtubules of the canal and, therefore, of the pellicle. A band of para-reservoir microtubules (PMT) acts as a linkage between the edges of the dorsal band at the formation of the canal. The third band of microtubules (MTR), more ventral, branches away from the reservoir-canal transition region and forms a supportive band for a pocket formed from the reservoir membrane. The outer part of the pocket membrane is closely invested with a fibrillar mesh. The pocket of Colacium, a green euglenoid, resembles structurally the cytopharynx of the colorless phagotrophic euglenoids, Isonema papillatum and the bodonid flagellates. The homologies support the hypothesis of euglenoid derivation from the kinetoplastid flagellates.     

Effects of gel processing on the properties of humic acid isolated from the alga Pilayella littoralis: A humic acid aerogel

Humic acid in the live alga Pilayellalittoralis was isolated as an aqueous gel by a standard sequential extraction method augmented with removal of alginic acid. Portions of the aqueous gel were (1) vacuum oven dried at 40 °C, (2) freeze freeze dried after cooling in liquid N₂, and (3) dried with supercritical fluid CO₂ after substitution of water in the gel with acetone. This paper compares the analytical and spectral properties of the products with compost derived HA and reports significant differences in their surface areas, packing densities, water retention, solute sorption and metal binding properties. The results are discussed in terms of different product morphologies determined by scanning electron microscopy. The aerogel obtained by supercritical fluid CO2 drying of an HA gel from Pilayella has the highest surface area (188 m² g^-1) reported for a humic acid. This revised version was published online in August 2006 with corrections to the Cover Date.     

Binding of aromatic isonitriles to haemoglobin and myoglobin.

A series of aromatic isonitriles were synthesized and their binding to sheep haemoglobin and horse heart myoglobin was investigated. The disubstituted ligands 2,6-dimethylphenylisonitrile and 2,6-diethylphenylisonitrile were found to bind to horse-heart myoglobin with affinities ranging from 500 to 5000 times greater than that of ethylisonitrile (4.6 x 10(-6) M) which has been the tightest binding isonitrile ligand for myoglobin thus far reported. The tight binding was not found to vary significantly with pH or temperature. An explanation for the unexpectedly high affinity is offered in terms of the electronic structure of aromatic isonitriles.     

In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity.

Site-specific mutagenesis was used to introduce amino acid substitutions at the asparagine codons of four conserved potential N-linked glycosylation sites within the gp120 envelope protein of human immunodeficiency virus (HIV). One of these alterations resulted in the production of noninfectious virus particles. The amino acid substitution did not interfere with the synthesis, processing, and stability of the env gene polypeptides gp120 and gp41 or the binding of gp120 to its cellular receptor, the CD4 (T4) molecule. Vaccinia virus recombinants containing wild-type or mutant HIV env genes readily induced syncytia in CD4+ HeLa cells. These results suggest that alterations involving the second conserved domain of the HIV gp120 may interfere with an essential early step in the virus replication cycle other than binding to the CD4 receptor. In long-term cocultures of a T4+ lymphocyte cell line and colon carcinoma cells producing the mutant virus, revertant infectious virions were detected. Molecular characterization of two revertant proviral clones revealed the presence of the original mutation as well as a compensatory amino acid change in another region of HIV gp120.