The role of Herceptin in early breast cancer

Herceptin is widely regarded as the most important development in the treatment of breast cancer since Tamoxifen and the development of the multidisciplinary team (MDT). It is particularly exciting from an oncological polint of view as it represents success in the emerging field of specific targeted therapies to specific molecular abnormalities in tumour cells. This review will focus on the nature of the Her2 overexpression and the role of herceptin in the treatment of early breast cancer.     

Wnt signaling in kidney development and disease

The Wnt gene family, which encodes secreted growth and differentiation factors, has been implicated in kidney organogenesis. The Wnts control both ureteric bud development and signaling, but they also serve as inductive factors to regulate nephrogenesis in the mesenchcymal cells. Several of the Wnt genes are expressed in the developing kidney, and gene knock-out studies have revealed specific developmental functions for these. Consistent with this, changes in Wnt ligands and pathway components are associated with many kidney diseases, including kidney cancers, renal fibrosis, cystic kidney diseases, acute renal failure, diabetic nephropathy and ischaemic injury. It is these associations of the Wnt signaling system with kidney development and kidney diseases that form to topic of this review.Key words: Wnt signaling, tubule induction, ureter development, kidney diseases, kidney cancer     

Development of novel tail-modified anandamide analogs

To explore the hydrophobic groove subsite within the CB1 cannabinoid receptor we have designed and synthesized a group of tail-substituted anandamide analogs. Our design involves the introduction of aryl or heterocyclic ring as terminal substituents that are connected to the last cis-arachidonyl double bond through aliphatic chains of variable lengths. Our results indicate that there are strict stereochemical requirements for the interaction of such analogs with the CB1 receptor. The optimal pharmacophore includes the phenyl, p-substituted phenyl, or 3-furyl substituents attached to the cis-double bond through a four methylene chain.     

Discovery of a potent and selective aurora kinase inhibitor

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.     

GPR30 contributes to estrogen-induced thymic atrophy

The mechanisms by which prolonged estrogen exposures, such as estrogen therapy and pregnancy, reduce thymus weight, cellularity, and CD4 and CD8 phenotype expression, have not been well defined. In this study, the roles played by the membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), and the intracellular estrogen receptors, estrogen receptor alpha (ERalpha) and beta (ERbeta), in 17beta-estradiol (E2)-induced thymic atrophy were distinguished by construction and the side-by-side comparison of GPR30-deficient mice with ERalpha and ERbeta gene-deficient mice. Our study shows that whereas ERalpha mediated exclusively the early developmental blockage of thymocytes, GPR30 was indispensable for thymocyte apoptosis that preferentially occurs in T cell receptor beta chain(-/low) double-positive thymocytes. Additionally, G1, a specific GPR30 agonist, induces thymic atrophy and thymocyte apoptosis, but not developmental blockage. Finally, E2 treatment attenuates the activation of nuclear factor-kappa B in CD25(-)CD4(-)CD8(-) double-negative thymocytes through an ERalpha-dependent yet ERbeta- and GPR30-independent pathway. Differential inhibition of nuclear factor-kappaB by ERalpha and GPR30 might underlie their disparate physiological effects on thymocytes. Our study distinguishes, for the first time, the respective contributions of nuclear and membrane E2 receptors in negative regulation of thymic development.     

Optimal analytical conditions for catalase in fresh water prawn, Macrobrachium malcolmsonii

The cytosol of hepatopancreas was prepared from the freshwater prawn Macrobrachium malcolmsonii, and optimal assay conditions, i.e., concentration of substrate, pH, and temperature, were determined to measure basal activities and kinetic constants of catalase activity. The properties of catalase were examined in M. macolmsonii, because quantitative data on catalase are limited in crustacean species. The optimal pH for catalase was 7.0. The activation energy was 3.55 Kcal/mol and energy inhibition value was 5.16 Kcal/mol. The value of energy inhibition is higher than that of energy activation. This may be due to inhibition of catalase by some substrate other than H2O2. A Km of 66.6 mM was also determined from various concentrations of substrate.     

Inhibition of matrix metalloproteinases improves left ventricular function in mice lacking osteopontin after myocardial infarction

Osteopontin (OPN) plays an important role in left ventricular (LV) remodeling after myocardial infarction (MI) by promoting collagen synthesis and accumulation. This study tested the hypothesis that MMP inhibition modulates post-MI LV remodeling in mice lacking OPN. Wild-type (WT) and OPN knockout (KO) mice were treated daily with MMP inhibitor (PD166793, 30 mg/kg/day) starting 3 days post-MI. LV functional and structural remodeling was measured 14 days post-MI. Infarct size was similar in WT and KO groups with or without MMP inhibition. M-mode echocardiography showed greater increase in LV end-diastolic (LVEDD) and end-systolic diameters (LVESD) and decrease in percent fractional shortening (%FS) and ejection fraction in KO-MI versus WT-MI. MMP inhibition decreased LVEDD and LVESD, and increased %FS in both groups. Interestingly, the effect was more pronounced in KO-MI group versus WT-MI (P < 0.01). MMP inhibition significantly decreased post-MI LV dilation in KO-MI group as measured by Langendorff-perfusion analysis. MMP inhibition improved LV developed pressures in both MI groups. However, the improvement was significantly higher in KO-MI group versus WT-MI (P < 0.05). MMP inhibition increased heart weight-to-body weight ratio, myocyte cross-sectional area, fibrosis and septal wall thickness only in KO-MI. Percent apoptotic myocytes in the non-infarct area was not different between the treatment groups. Expression and activity of MMP-2 and MMP-9 in the non-infarct area was higher in KO-MI group 3 days post-MI. MMP inhibition reduced MMP-2 activity in KO-MI with no effect on the expression of TIMP-2 and TIMP-4 14 days post-MI. Thus, activation of MMPs contributes to reduced fibrosis and LV dysfunction in mice lacking OPN.     

On the impact of correlation between collaterally consanguineous cells on lymphocyte population dynamics

During an adaptive immune response, lymphocytes proliferate for five to twenty-five cell divisions, then stop and die over a period of weeks. Based on extensive flow cytometry data, Hawkins et al. (Proc Natl Acad Sci USA 104:5032–5037, 2007) introduced a cell-level stochastic model of lymphocyte population dynamics, called the Cyton Model, that accurately captures mean lymphocyte population size as a function of time. In Subramanian et al. (J Math Biol 56(6):861–892, 2008), we performed a branching process analysis of the Cyton Model and deduced from parameterizations for in vitro and in vivo data that the immune response is predictable despite each cell’s fate being highly variable. One drawback of flow cytometry data is that individual cells cannot be tracked, so that it is not possible to investigate dependencies in the fate of cells within family trees. In the absence of this information, while the Cyton Model abandons one of the usual assumptions of branching processes (the independence of lifetime and progeny number), it adopts another of the standard branching processes hypotheses: that the fates of progeny are stochastically independent. However, new experimental observations of lymphocytes show that the fates of cells in the same family tree are not stochastically independent. Hawkins et al. (2008, submitted) report on ciné lapse photography experiments where every founding cell’s family tree is recorded for a system of proliferating lymphocytes responding to a mitogenic stimulus. Data from these experiments demonstrate that the death-or-division fates of collaterally consanguineous cells (those in the same generation within a founding cell’s family tree) are strongly correlated, while there is little correlation between cells of distinct generations and between cells in distinct family trees. As this finding contrasts with one of the assumptions of the Cyton Model, in this paper we introduce three variants of the Cyton Model with increasing levels of collaterally consanguineous correlation structure to incorporate these new found dependencies. We investigate their impact on the predicted expected variability of cell population size. Mathematically we conclude that while the introduction of correlation structure leaves the mean population size unchanged from the Cyton Model, the variance of the population size distribution is typically larger. Biologically, through comparison of model predictions for Cyton Model parameterizations determined by in vitro and in vivo experiments, we deduce that if collaterally consanguineous correlation extends beyond cousins, then the immune response is less predictable than would be concluded from the original Cyton Model. That is, some of the variability seen in data that we previously attributed to experimental error could be due to intrinsic variability in the cell population size dynamics.      

Effect of process parameters on 3-hydroxypropionic acid production from glycerol using a recombinant <Emphasis Type="Italic">Escherichia coli</Emphasis>

The stability and specific activity of endo-β-1,4-glucanase III from Trichoderma reesei QM9414 was enhanced, and the expression efficiency of its encoding gene, egl3, was optimized by directed evolution using error-prone PCR and activity screening in Escherichia coli RosettaBlue (DE3) pLacI as a host. Relationship between increase in yield of active enzyme in the clones and improvement in its stability was observed among the mutants obtained in the present study. The clone harboring the best mutant 2R4 (G41E/T110P/K173M/Y195F/P201S/N218I) selected in via second-round mutagenesis after optimal recombinating of first-round mutations produced 130-fold higher amount of mutant enzyme than the transformant with wild-type EG III. Mutant 2R4 produced by the clone showed broad pH stability (4.4–8.8) and thermotolerance (entirely active at 55°C for 30 min) compared with those of the wild-type EG III (pH stability, 4.4–5.2; thermostability, inactive at 55°C for 30 min). k _cat of 2R4 against carboxymethyl-cellulose was about 1.4-fold higher than that of the wild type, though the K _m became twice of that of the wild type.     

Utility of Eucalyptus tereticornis (Smith) bark and Desulfotomaculum nigrificans for the remediation of acid mine drainage

The efficacy of the bark of Eucalyptus tereticornis (Smith) as an adsorbent for the removal of metal ions and sulphate from acid mine water was assessed. About 96% of Fe, 75% of Zn, 92% of Cu and 41% of sulphate removal was achieved from the acid mine water of pH 2.3 with a concomitant increase in pH value by about two units after interaction with the tree bark, under appropriate conditions. The adsorption isotherms adhered to Freundlich and Langmuir relationships and were exothermic in nature. The free energy of the adsorption process was found to be negative attesting to the feasibility of the reaction. The adsorption kinetics followed the first-order Lagergren rate equation. The filtrate obtained after treatment with E. tereticornis (Sm) bark was found to contain essential elements like potassium, magnesium, calcium, sodium and phosphate apart from carbon which served as a successful growth medium for the sulphate reducing bacteria (SRB) namely Desulfotomaculum nigrificans. Bacterial growth studies showed that about 57% and 72% of sulphate reduction could be achieved at initial pH values of 4.1 and 5.5 respectively of the acid mine water. Pretreatment of the acid mine water with tree bark followed by bioremoval using Dsm. nigrificans resulted in about 75% and 84% respectively of sulphate reduction at pH 4.1 and 5.5, cumulatively by biosorption and bioreduction. The mechanisms of metal ion removal using tree bark and sulphate reduction using Dsm. nigrificans are discussed.