Optimal response to chemotherapy for a mathematical model of tumor–immune dynamics

An optimal control problem for cancer chemotherapy is considered that includes immunological activity. In the objective a weighted average of several quantities that describe the effectiveness of treatment is minimized. These terms include (i) the number of cancer cells at the terminal time, (ii) a measure for the immunocompetent cell densities at the terminal point (included as a negative term), (iii) the overall amount of cytotoxic agents given as a measure for the side effects of treatment and (iv) a small penalty on the terminal time that limits the overall therapy horizon which is assumed to be free. This last term is essential in obtaining a well-posed problem formulation. Employing a Gompertzian growth model for the cancer cells, for various scenarios optimal controls and corresponding responses of the system are calculated. Solutions initially follow a full dose treatment, but then at one point switch to a singular regimen that only applies partial dosages. This structure is consistent with protocols that apply an initial burst to reduce the tumor volume and then maintain a small volume through lower dosages. Optimal controls end with either a prolonged period of no dose treatment or, in a small number of scenarios, this no dose interval is still followed by one more short burst of full dose treatment.     

Binding of the new morphiceptin analogs to human MCF-7 breast cancer cells and their effect on growth

In the present study, we reported on the synthesis of two new mu-opioid peptide analogs, [D-1-Nal3]morphiceptin and [D-1-Nal4]-morphiceptin [1-Nal=3-(1-naphthyl)-alanine] which expressed receptor binding affinities at least at the level of the primary opioid ligands. The new analogs also labeled mu-opioid receptors on the cells of human breast cancer MCF-7 cell line with affinity much higher than that of endomorphins and morphiceptin, the well-known mu-selective opioid peptides. However, none of the tested peptides significantly decreased cell proliferation of MCF-7 cells.     

Fenotypic and genotypic characterization of Shiga toxin-producing Escherichia coli O111 strain isolated from patient with hemolytic-uremic syndrome

Shiga toxin-producing E. coli O157 and non-O157 are important emergance pathogens that can cause diarrhea and hemorrhagic colitis with life-threatening complications, such as hemolytic uremic syndrome (HUS). A few cases of EHEC infections are documented per year in Poland. Among them only one patient with EHEC O157 infection developed HUS. We characterized the first VTEC non-O157 strain isolated from child with HUS in Poland. The VTEC O111 strain produced Stx2 which was cytotoxic for Vero cell. Using DNA microarray analysis we have found set of virulence genes in VTEC O111 strain as: stx2A, stx2B, ehly, eae, tir tccP espA, espJ, cif nleA, nleB, lpfA, iha, efa1, cba. The strain was fenotypic resistant to streptomycin, tetracyclin and sulphonamides (strA, tetA, sul2 genes were detected).     

Ecological attributes recorded in stable isotope ratios of arboreal prosimian hair

Carbon and nitrogen stable isotope ratios were measured in hair samples from two species of Galago from Gedi Ruins National Monument in eastern Kenya and from Lepilemur leucopus from Beza Mahafaly Special Reserve in southern Madagascar. Forest structure was generally similar in the two areas but average rainfall was lower in Madagascar. Species average ¹³C values varied with feeding height in the forest canopy and with average rainfall level as expected from reported variation in plant ¹³C values. G. garnettii, which feeds higher in the forest canopy, had less negative ¹³C values than G. zanzibaricus, which spends more time below 5 m. L. leucopus, from a drought-afflicted forest, had less negative hair ¹³C values than the two galago species. The values within the Lepilemur sample showed a positive linear relation with percent dependence on a CAM tree species and with xeric conditions within the species reserve. Nitrogen stable isotope ratios varied with trophic level of feeding and with time spent feeding on leguminous plants. The insectivorous galagos had significantly more positive ¹⁵N values than the folivorous L. leucopus. Within the Lepilemur sample, ¹⁵N values varied inversely with the percent of feeding time spent on leguminous plants. The range of ¹⁵N and ¹³C values in each of the prosimian species is larger than reported for animals fed monotonous diets and for New World monkey species. The monkey species feed as groups of individuals whereas the prosimians have solitary feeding habits. The ranges in the prosimian species apparently reflect the greater variation in diet among individual prosimians compared to individual monkeys. The isotope data reported here are equivalent, on average, to those reported for other arboreal species from similar forest habitats and with similar dietary habits. This supports the use of such data for paleoecological reconstruction of forest and woodland systems and diet reconstruction of extinct primate populations and species. Received: 18 April 1997 / Accepted: 11 August 1997     

Polyphenols of Rosa L. leaves extracts and their radical scavenging activity

Antioxidant potential of Rosa L. leaves methanolic extracts was evaluated in vitro using a spectrophotometric method based on measuring the radical scavenging effect on 2,2-di-phenyl-1-picrylhydrazyl (DPPH) radicals. The contents of ellagic acid, quercetin and kaempferol in the extracts from leaves of seventeen rose species were determined using SPE-RP-HPLC methods. Additionally, total phenolic content was determined spectrophotometrically according to the Folin-Ciocalteu procedure and calculated as gallic acid equivalents (GAE). Remarkable high antioxidant activity and high total phenolic content (5.7% < GAE < 15.2%), large ellagic acid (EA) content from 9.37 to 19.42 mg/g of dry weight, a quercetin content ranging from 3.68 to 15.81 mg/g of dry weight and kaempferol content from 1.25 to 9.41mg/g of dry weight were found in rose leaves. Significant correlation between EA (r(2) = 0.6131), quercetin (r(2) = 0.5158), total phenolic content (r(2)= 0.8485) and antioxidant activity was observed. Basing on the studies conducted one may assume that the extracts of rose leaves are a rich source of natural antioxidants and could be used to prevent free-radical-induced deleterious effects.     

Time-related changes of motor unit properties in the rat medial gastrocnemius muscle after the spinal cord injury. II. Effects of a spinal cord hemisection

The contractile properties of motor units (MUs) were investigated in the medial gastrocnemius (MG) muscle in rats after the spinal cord hemisection at a low thoracic level. Hemisected animals were divided into 4 groups: 14, 30, 90 and 180 days after injury. Intact rats formed a control group. The mass of the MG muscle did not change significantly after spinal cord hemisection, hind limb locomotor pattern was almost unchanged starting from two weeks after injury, but contractile properties of MUs were however altered. Contraction time (CT) and half-relaxation time (HRT) of MUs were prolonged in all investigated groups of hemisected rats. The twitch-to-tetanus ratio (Tw/Tet) of fast MUs after the spinal cord hemisection increased. For slow MUs Tw/Tet values did not change in the early stage after the injury, but significantly decreased in rats 90 and 180 days after hemisection. As a result of hemisection the fatigue resistance especially of slow and fast resistant MU types was reduced, as well as fatigue index (Fat I) calculated for the whole examined population of MUs decreased progressively with the time. After spinal cord hemisection a reduced number of fast MUs presented the sag at frequencies 30 and 40 Hz, however more of them revealed sag in 20 Hz tetanus in comparison to control group. Due to considerable changes in twitch contraction time and disappearance of sag effect in unfused tetani of some MUs in hemisected animals, the classification of MUs in all groups of rats was based on the 20 Hz tetanus index (20 Hz Tet I) but not on the standard criteria usually applied for MUs classification. MU type differentiations demonstrated some clear changes in MG muscle composition in hemisected animals consisting of an increase in the proportion of slow MUs (likely due to an increased participation of the studied muscle in tonic antigravity activity) together with an increase in the percentage of fast fatigable MUs.     

Immunolocalization and expression of kinin B1R and B2R receptors in human inflammatory bowel disease

Bradykinin is a mediator of inflammation, responsible for pain, vasodilation, and capillary permeability. Bradykinin receptor 1 (B(1)R) and bradykinin receptor 2 (B(2)R) are G protein-coupled receptors that mediate kinin effects. The latter is constitutive and rapidly desensitized; the former is induced by inflammatory cytokines and resistant to densensitization. The distribution of bradykinin receptors in human intestinal tissue was studied in patients with inflammatory bowel disease (IBD), namely ulcerative colitis (UC) and Crohn's disease (CD). Both B(2)R and B(1)R proteins are expressed in the epithelial cells of normal and IBD intestines. B(1)R protein is visualized in macrophages at the center of granulomas in CD. B(2)R protein is normally present in the apexes of enterocytes in the basal area and intracellularly in inflammatory tissue. In contrast, B(1)R protein is found in the basal area of enterocytes in normal intestine but in the apical portion of enterocytes in inflamed tissue. B(1)R protein is significantly increased in both active UC and CD intestines compared with controls. In patients with active UC, B(1)R mRNA is significantly higher than B(2)R mRNA. However, in inactive UC patients, the B(1)R and B(2)R mRNA did not differ significantly. Thus bradykinin receptors in IBD may reflect intestinal inflammation. Increased B(1)R gene and protein expression in active IBD provides a structural basis of the important role of bradykinin in chronic inflammation.     

The hepatitis C virus NS2 protein is an inhibitor of CIDE-B-induced apoptosis

Chronic hepatitis C virus (HCV) infection frequently leads to liver cancer. To determine the viral factor(s) potentially involved in viral persistence, we focused our work on NS2, a viral protein of unknown function. To assign a role for NS2, we searched for cellular proteins that interact with NS2. Performing a two-hybrid screen on a human liver cDNA library, we found that NS2 interacted with the liver-specific pro-apoptotic CIDE-B protein. Binding specificity of NS2 for CIDE-B was confirmed by cell-free assays associated with colocalization studies and coprecipitation experiments on human endogenous CIDE-B. CIDE-B, a member of the novel CIDE family of apoptosis-inducing factors, has been reported to show strong cell death-inducing activity in its C-terminal domain. We show that this CIDE-B killing domain is involved in the NS2 interaction. NS2 binding was sufficient to inhibit CIDE-B-induced apoptosis because an NS2 deletion mutant unable to interact with CIDE-B in vitro lost its capacity to interfere with CIDE-B cell death activity. Although it has been reported that CIDE-B-induced apoptosis is characterized by mitochondrial localization, the precise apoptotic mechanism remained unknown. Here, we show that CIDE-B induced cell death in a caspase-dependent manner through cytochrome c release from mitochondria. Furthermore, we found that NS2 counteracted the cytochrome c release induced by CIDE-B. In vivo, the CIDE-B protein level was extremely low in adenovirus-infected transgenic mice expressing the HCV polyprotein compared with that in wild-type mice. We suggest that NS2 interferes with the CIDE-B-induced death pathway and participates in HCV strategies to subvert host cell defense.     

Comparative Large-Scale Analysis of Interactions between Several Crop Species and the Effector Repertoires from Multiple Pathovars of Pseudomonas and Ralstonia

Bacterial plant pathogens manipulate their hosts by injection of numerous effector proteins into host cells via type III secretion systems. Recognition of these effectors by the host plant leads to the induction of a defense reaction that often culminates in a hypersensitive response manifested as cell death. Genes encoding effector proteins can be exchanged between different strains of bacteria via horizontal transfer, and often individual strains are capable of infecting multiple hosts. Host plant species express diverse repertoires of resistance proteins that mediate direct or indirect recognition of bacterial effectors. As a result, plants and their bacterial pathogens should be considered as two extensive coevolving groups rather than as individual host species coevolving with single pathovars. To dissect the complexity of this coevolution, we cloned 171 effector-encoding genes from several pathovars of Pseudomonas and Ralstonia. We used Agrobacterium tumefaciens-mediated transient assays to test the ability of each effector to induce a necrotic phenotype on 59 plant genotypes belonging to four plant families, including numerous diverse accessions of lettuce (Lactuca sativa) and tomato (Solanum lycopersicum). Known defense-inducing effectors (avirulence factors) and their homologs commonly induced extensive necrosis in many different plant species. Nonhost species reacted to multiple effector proteins from an individual pathovar more frequently and more intensely than host species. Both homologous and sequence-unrelated effectors could elicit necrosis in a similar spectrum of plants, suggesting common effector targets or targeting of the same pathways in the plant cell.