Cytotoxic targeting of F9 teratocarcinoma tumours with anti-ED-B fibronectin scFv antibody modified liposomes

We prepared small unilamellar liposomes derivatised with single chain antibody fragments specific for the ED-B domain of B-fibronectin. This extracellular matrix associated protein is expressed around newly forming blood vessels in the vicinity of many types of tumours. The single chain antibody fragments were functionalised by introduction of C-terminal cysteines and linked to liposomes via maleimide groups located at the terminal ends of poly(ethylene glycol) modified phospholipids. The properties of these anti-ED-B single chain antibody fragments-liposomes were analysed in vitro on ED-B fibronectin expressing Caco-2 cells and in vivo by studying their biodistribution and their therapeutic potential in mice bearing subcutanous F9 teratocarcinoma tumours. Radioactively labelled (114mIndium) single chain antibody fragments-liposomes accumulated in the tumours at 2–3-fold higher concentrations during the first 2 h after i.v. injection compared to unmodified liposomes. After 6–24 h both liposome types were found in similar amounts (8–10% injected dose g−1) in the tumours. Animals treated i.v. with single chain antibody fragments-liposomes containing the new cytotoxic agent 2′-deoxy-5-fluorouridylyl-N4-octadecyl-1-β-D-arabinofuranosylcytosine (30 mg kg-1 per dose, five times every 24 h) showed a reduction of tumour growth by 62–90% determined on days 5 and 8, respectively, compared to animals receiving control liposomes. Histological analysis revealed a marked reduction of F9 tumour cells and excessive deposition of fibronectin in the extracellular matrix after treatment with single chain antibody fragments-2-dioxy-5-fluorouridylyl-N4-octadecyl-1-β-D-arabinofuranosylcytosine-liposomes. Single chain antibody fragments-liposomes targeted to ED-B fibronectin positive tumours therefore represent a promising and versatile novel drug delivery system for the treatment of tumours

Generation of recombinant single-chain antibodies neutralizing the cytolytic activity of vaginolysin, the main virulence factor of Gardnerella vaginalis

Generated scFvs is the first example of recombinant single-chain antibodies with VLY-neutralizing activity produced in prokaryote expression system. G. vaginalis caused infections continue to be a world-wide problem, therefore neutralizing recombinant antibodies may provide novel therapeutic agents useful in the treatment of bacterial vaginosis and other diseases caused by G. vaginalis

Physicochemical attack against solid tumors based on the reversal of direction of entropy flow: an attempt to introduce thermodynamics in anticancer therapy

BACKGROUND: There are many differences between healthy tissue and growing tumor tissue, including metabolic, structural and thermodynamic differences. Both structural and thermodynamic differences can be used to follow the entropy differences in cancerous and normal tissue. Entropy production is a bilinear form of the rates of irreversible processes and the corresponding "generalized forces". Entropy production due to various dissipation mechanisms based on temperature differences, chemical potential gradient, chemical affinity, viscous stress and exerted force is a promising tool for calculations relating to potential targets for tumor isolation and demarcation. METHODS: The relative importance of five forms of entropy production was assessed through mathematical estimation. Using our mathematical model we demonstrated that the rate of entropy production by a cancerous cell is always higher than that of a healthy cell apart from the case of the application of external energy. Different rates of entropy production by two kinds of cells influence the direction of entropy flow between the cells. Entropy flow from a cancerous cell to a healthy cell transfers information regarding the cancerous cell and propagates its invasive action to the healthy tissues. To change the direction of entropy flow, in addition to designing certain biochemical pathways to reduce the rate of entropy production by cancerous cells, we suggest supplying external energy to the tumor area, changing the relative rate of entropy production by the two kinds of cells and leading to a higher entropy accumulation in the surrounding normal cells than in the tumorous cells. CONCLUSION: Through the use of mathematical models it was quantitatively demonstrated that when no external force field is applied, the rate of entropy production of cancerous cells is always higher than that of healthy cells. However, when the external energy of square wave electric pulses is applied to tissues, the rate of entropy production of normal cells may exceed that of cancerous cells. Consequently, the application of external energy to the body can reverse the direction of the entropy current. The harmful effect brought about by the entropy flow from cancerous to healthy tissue can be blocked by the reversed direction of entropy current from the irradiated normal tissue around the tumor

Gravitational sliding of the Mt. Etna massif along a sloping basement

Geological field evidence and laboratory modelling indicate that volcanoes constructed on slopes slide downhill. If this happens on an active volcano, then the movement will distort deformation data and thus potentially compromise interpretation. Our recent GPS measurements demonstrate that the entire edifice of Mt. Etna is sliding to the ESE, the overall direction of slope of its complex, rough sedimentary basement. We report methods of discriminating the sliding vector from other deformation processes and of measuring its velocity, which averaged 14 mm year−1 during four intervals between 2001 and 2012. Though sliding of one sector of a volcano due to flank instability is widespread and well-known, this is the first time basement sliding of an entire active volcano has been directly observed. This is important because the geological record shows that such sliding volcanoes are prone to devastating sector collapse on the downslope side, and whole volcano migration should be taken into account when assessing future collapse hazard. It is also important in eruption forecasting, as the sliding vector needs to be allowed for when interpreting deformation events that take place above the sliding basement within the superstructure of the active volcano, as might occur with dyke intrusion or inflation/deflation episodes

Tumour-targeted nanomedicines: principles and practice

Drug targeting systems are nanometre-sized carrier materials designed for improving the biodistribution of systemically applied (chemo)therapeutics. Various different tumour-targeted nanomedicines have been evaluated over the years, and clear evidence is currently available for substantial improvement of the therapeutic index of anticancer agents. Here, we briefly summarise the most important targeting systems and strategies, and discuss recent advances and future directions in the development of tumour-targeted nanomedicines

Possible extracardiac predictors of aortic dissection in Marfan syndrome

BACKGROUND: According to previous studies, aortic diameter alone seems to be insufficient to predict the event of aortic dissection in Marfan syndrome (MFS). Determining the optimal schedule for preventive aortic root replacement (ARR) aortic growth rate is of importance, as well as family history, however, none of them appear to be decisive. Thus, the aim of this study was to search for potential predictors of aortic dissection in MFS. METHODS: A Marfan Biobank consisting of 79 MFS patients was established. Thirty-nine MFS patients who underwent ARR were assigned into three groups based on the indication for surgery (dissection, annuloaortic ectasia and prophylactic surgery). The prophylactic surgery group was excluded from the study. Transforming growth factor-beta (TGF-beta) serum levels were measured by ELISA, relative expression of c-Fos, matrix metalloproteinase 3 and 9 (MMP-3 and -9) were assessed by RT-PCR. Clinical parameters, including anthropometric variables - based on the original Ghent criteria were also analyzed. RESULTS: Among patients with aortic dissection, TGF-beta serum level was elevated (43.78 +/- 6.51 vs. 31.64 +/- 4.99 ng/l, p < 0.0001), MMP-3 was up-regulated (Ln2alpha = 1.87, p = 0.062) and striae atrophicae were more common (92% vs. 41% p = 0.027) compared to the annuloaortic ectasia group. CONCLUSIONS: We found three easily measurable parameters (striae atrophicae, TGF-beta serum level, MMP-3) that may help to predict the risk of aortic dissection in MFS. Based on these findings a new classification of MFS, that is benign or malignant is also proposed, which could be taken into consideration in determining the timing of prophylactic ARR

A search for the decay modes B+/- to h+/- tau l

We present a search for the lepton flavor violating decay modes B+/- to h+/- tau l (h= K,pi; l= e,mu) using the BaBar data sample, which corresponds to 472 million BBbar pairs. The search uses events where one B meson is fully reconstructed in one of several hadronic final states. Using the momenta of the reconstructed B, h, and l candidates, we are able to fully determine the tau four-momentum. The resulting tau candidate mass is our main discriminant against combinatorial background. We see no evidence for B+/- to h+/- tau l decays and set a 90% confidence level upper limit on each branching fraction at the level of a few times 10^-5.Comment: 15 pages, 7 figures, submitted to Phys. Rev.

Evidence for an excess of B -> D(*) Tau Nu decays

Based on the full BaBar data sample, we report improved measurements of the ratios R(D(*)) = B(B -> D(*) Tau Nu)/B(B -> D(*) l Nu), where l is either e or mu. These ratios are sensitive to new physics contributions in the form of a charged Higgs boson. We measure R(D) = 0.440 +- 0.058 +- 0.042 and R(D*) = 0.332 +- 0.024 +- 0.018, which exceed the Standard Model expectations by 2.0 sigma and 2.7 sigma, respectively. Taken together, our results disagree with these expectations at the 3.4 sigma level. This excess cannot be explained by a charged Higgs boson in the type II two-Higgs-doublet model. We also report the observation of the decay B -> D Tau Nu, with a significance of 6.8 sigma.Comment: Expanded section on systematics, text corrections, improved the format of Figure 2 and included the effect of the change of the Tau polarization due to the charged Higg

Search for the decay modes D^0 → e^+e^-, D^0 → μ^+μ^-, and D^0 → e^±μ∓

We present searches for the rare decay modes D^0→e^+e^-, D^0→μ^+μ^-, and D^0→e^±μ^∓ in continuum e^+e^-→cc events recorded by the BABAR detector in a data sample that corresponds to an integrated luminosity of 468  fb^(-1). These decays are highly Glashow–Iliopoulos–Maiani suppressed but may be enhanced in several extensions of the standard model. Our observed event yields are consistent with the expected backgrounds. An excess is seen in the D^0→μ^+μ^- channel, although the observed yield is consistent with an upward background fluctuation at the 5% level. Using the Feldman–Cousins method, we set the following 90% confidence level intervals on the branching fractions: B(D^0→e^+e^-)<1.7×10^(-7), B(D^0→μ^+μ^-) within [0.6,8.1]×10^(-7), and B(D^0→e^±μ^∓)<3.3×10^(-7)

Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

We study the process $e^+e^-\to J/\psi\pi^{+}\pi^{-}$ with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 $\mathrm{fb^{-1}}$. We investigate the $J/\psi \pi^{+}\pi^{-}$ mass distribution in the region from 3.5 to 5.5 $\mathrm{GeV/c^{2}}$. Below 3.7 $\mathrm{GeV/c^{2}}$ the $\psi(2S)$ signal dominates, and above 4 $\mathrm{GeV/c^{2}}$ there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 $\mathrm{GeV/c^{2}}$ yields a mass value $4244 \pm 5$ (stat) $\pm 4$ (syst)$\mathrm{MeV/c^{2}}$ and a width value $114 ^{+16}_{-15}$ (stat)$\pm 7$(syst)$\mathrm{MeV}$ for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 $\mathrm{GeV/c^{2}}$. In addition, we investigate the $\pi^{+}\pi^{-}$ system which results from Y(4260) decay