Changes in intratumor heterogeneity in blood perfusion in intradermal human melanoma xenografts during tumor growth assessed by DCE-MRI

The purpose of this study was to use dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to search for systematic intratumor heterogeneity in blood perfusion in human melanoma xenografts growing intradermally in BALB/c-nu/nu mice. Six xenografted tumors of an amelanotic human melanoma line (A-07) were included in the study. DCE-MRI was performed daily for 5 days by using spoiled-gradient recalled sequences. Tumor images of E.F (E is initial extraction fraction and F is perfusion) were produced by subjecting DCE-MRI data to Kety analysis. E.F was used as a measure of tumor blood perfusion, since comparative studies have shown that E.F is closely related to blood perfusion in A-07 tumors. The E.F images indicated that the intratumor heterogeneity in blood perfusion was similar in all investigated tumors. The blood perfusion was low in the center of the tumors and increased toward the tumor periphery in the dorsal and ventral direction by a factor of 3-4, but not in the lateral and medial direction. The magnitude of the heterogeneity increased by a factor of approximately 2 during tumor growth. In conclusion, intradermal human melanoma xenografts show significant systematic intratumor heterogeneity in blood perfusion.     

Intratumor heterogeneity in perfusion in human melanoma xenografts measured by contrast-enhanced magnetic resonance imaging

The perfusion in tumors shows substantial spatial heterogeneity compared to that in normal tissues. The aim of the present study was to evaluate the intratumor heterogeneity in perfusion in tumors of two amelanotic human melanoma xenograft lines, A-07 and R-18, grown intradermally in Balb/c nu/nu mice. A non-invasive contrast-enhanced magnetic resonance imaging method yielding results in absolute values was applied. The perfusion was determined in manually defined regions of interest, corresponding to a whole tumor or to subregions of a tumor. The mean perfusion and the intertumor heterogeneity in perfusion were similar for the two tumor lines. For whole A-07 tumors, the perfusion ranged from 0.089 mL/(g . min) to 0.20 mL/(g . min) [mean: 0.15 mL/(g . min)], and for whole R-18 tumors, from 0.030 mL/(g . min) to 0.17 mL/(g . min) [mean: 0.13 mL/(g . min)]. The intratumor heterogeneity, on the other hand, was estimated to be 6.4 times larger in A-07 tumors than in R-18 tumors. The highest perfusion values, up to 0.69 mL/(g . min), were found in subregions of A-07 tumors. The intratumor heterogeneity was substantially larger than the intertumor heterogeneity in A-07 tumors, whereas in R-18 tumors, the intratumor heterogeneity was similar to the intertumor heterogeneity. These observations imply that measurements of mean tumor perfusion may have limited value as a predictive assay for outcome of treatment.     

Effects of hyperthermia on bioenergetic status and phosphorus T1S in human melanoma xenografts monitored by 31P-MRS.

Conventional hyperthermia enhances tumor response to radiotherapy through thermal cell inactivation and vascular shut-down, whereas mild hyperthermia potentiates the effect of radiotherapy by improving tumor oxygenation. The work reported here was aimed at investigating whether 31P-magnetic resonance spectroscopy (31P-MRS) measurements of tumor bioenergetic status; i.e., the (PCr + NTPbeta)/Pi resonance ratio, and/or the spin lattice relaxation times, T1s, of the Pi and NTPbeta resonances can be used to distinguish between the effects of conventional and mild hyperthermia. BEX-t human melanoma xenografts were treated at 43.0 degrees C for 15 or 60 min, and bioenergetic status and T1s were measured as function-of-time after treatment. Hyperthermia-induced effects on tumor blood flow was measured by using the 86Rb uptake method. The morphology of the capillary network in treated and untreated tumors was studied by histologic examination. Tumors treated for 15 min showed increased blood flow and dilated capillaries, whereas tumors treated for 60 min showed decreased blood flow and capillary occlusions; i.e., 43.0 degrees C for 15 min was a treatment consistent with mild hyperthermia and 43.0 degrees C for 60 min was consistent with conventional hyperthermia treatment of BEX-t tumors. Bioenergetic status increased after treatment at 43.0 degrees C for 15 min, and decreased after treatment at 43.0 degrees C for 60 min, similar to the blood flow. Likewise, the T1 of the Pi resonance increased after treatment at 43.0 degrees C for 15 min, and decreased after treatment at 43.0 degrees C for 60 min. The T1 of the NTPbeta resonance showed a similar change as the T1 of the Pi resonance, but less pronounced. Consequently, 31P-MRS measurements of tumor bioenergetic status and the T1 of the Pi resonance may perhaps be utilized to distinguish between vascular effects of mild and conventional hyperthermia.     

Systems of oblate molecules. Monte Carlo study

Monte Carlo (MC) simulations were performed for systems of hard oblate spherocylinders with breadth-to-height ratios φ = 0.5–3.5 and packing fractions y = 0.25–0.45 and for Kihara oblate molecule systems of φ = 1 at reduced temperatures T* = 0.75 and 1.0 and y = 0.05–0.45. The compression factors and the dependence of the average correlation functions on the shortest surface-to-surface distance were determined for the case of hard oblate spherocylinders and the compression factors, residual internal energies and average correlation functions for the case of the generalized Kihara molecule systems. In addition, values of the third virial coefficient of the hard oblate spherocylinders were evaluated in the range of φ = 1–3. Results of the MC simulations for the hard oblate spherocylinders compare well with the available data in the literature and theoretical values; thermodynamic functions of the Kihara molecule systems were determined from the second-order perturbation theory. They agree well with our MC values at lower densities and higher reduced temperatures.     

Surface States in a Simple Crystal Model

A very simple crystal model of a semi-infinite heteroatomic planar lattice like boronitride is investigated for the energy, wave functions and existence conditions of surface states, using the one-electron Green function method. σ and π electrons are treated separately. For π electrons, we find two surface state bands, both for the electropositive and the electronegative surface. The consequence is the existence of Shockley “subsurface” states. For σ electrons, similar results were found as for the sphalerite-type lattice. The investigated model can also be used to draw qualitative conclusions about the effect of electronic correlation on surface states of planar graphite. The possibility of finding a certain type of “antiferromagnetism” with π electrons localized on the planar graphite boundary is suggested. On étudie un modèle très simple d'un cristal avec un réseau sémi-infini, héteroatomique, comme le boronitride. L'énergie, les fonctions d'onde et des conditions d'existence d'états de surface ont été obtenus par la méthode de la fonction de Green à un électron. Les électrons σ et π ont été traités séparément. Pour les électrons π on trouve deux bandes d'états de surface pour la surface électropositive ainsi que pour la surface électronégative, ce qui implique l'existence d'états de “sous-surface” de Shockley. Pour les électrons σ on trouve des résultats semblables aux ceux qu'on a obtenu pour le réseau de type sphalérite. Le modèle étudié ici peut aussi être employé pour tirer des conclusions qualitatives sur l'effet de la corrélation électronique sur les états de surface du graphite plan. On propose qu'il serait possible de trouver un certain type de “antiferromagnétisme” avec les électrons π localisés sur le bord du graphite plan. Es wurde ein einfaches Modell für ein halb-unendliches, heteroatomares Kristallgitter, wie Boronitrid untersucht. Die Energie, die Wellenfunktionen und Existenzbedingungen für Oberflächenzustände wurden mit der Einelektron-Green-Funktionsmethode erhalten. Die σ- und π-Electronen wurden getrennt behandelt. Für die π-Elektronen finden wir zwei Bände für Oberflächenzustände, sowohl für die elektropositive als für die elektronegative Oberfläche. Als Folgerung erhalten wir die Shockleysche unteroberflächenzustände. Für die σ-Elektronen wurden ähnliche Resultate als für das Sphaleritgitter gefunden. Das untersuchte Modell kann auch dafür angewendet werden, urn den Effekt der elektronischen Korrelation auf die Oberflächenzustände planares Graphits in qualitativer Weise zu diskutieren. Es wurde vorgeschlagen, dass es möglich wäre, eine gewisse Art von “Antiferromagnetismus” der π-Elektronen die auf der Grenze planares Graphits lokalisiert sind, zu finden.     

Antibacterial Activity and Synergistic Effect of Biosynthesized AgNPs with Antibiotics Against Multidrug-Resistant Biofilm-Forming Coagulase-Negative Staphylococci Isolated from Clinical Samples

Silver nanoparticles form promising template for designing antimicrobial agents against drug resistant pathogenic microorganisms. Thus, the development of a reliable green approach for the synthesis of nanoparticles is an important aspect of current nanotechnology research. In the present investigation, silver nanoparticles synthesized by a soil Bacillus sp. were characterized using UV–vis spectroscopy, FTIR, SEM, and EDS. The antibacterial potential of biosynthesized silver nanoparticles, standard antibiotics, and their conjugates were evaluated against multidrug-resistant biofilm-forming coagulase-negative S. epidermidis strains, S. aureus, Salmonella Typhi, Salmonella Paratyphi, and V. cholerae. Interestingly, silver nanoparticles (AgNPs) showed remarkable antibacterial activity against all the test strains with the highest activity against S. epidermidis strains 145 and 152. In addition, the highest synergistic effect of AgNPs was observed with chloramphenicol against Salmonella typhi. The results of the study clearly indicate the promising biomedical applications of biosynthesized AgNPs.     

RELATIONSHIP BETWEEN SURVIVAL AND THYMINE-DIMER EXCISION IN ULTRAVIOLET-IRRADIATED ESCHERICHIA COLI

Abstract— The influence of amino acid prestarvation on both the resistance to u.v. light and excision of thymine dimers of bacterial strains E. coli B/r hcr ⁺ thy- trp ^-, E. coli B/r hcr ^-thy^- trp ^-, and E, coli 15 T^- 555–7 thy ^- meth ^- trp ^- arg ^- has been studied.
The prestarvation increased the resistance of all the strains but reasonably inhibited excision of thymine dimers. Thus the enhancement of u.v. resistance after amino acid prestarvation was not due to more complete excision of thymine dimers.     

Comparing Nonsmooth Nonconvex Bundle Methods in Solving Hemivariational Inequalities

Hemivariational inequalities can be considered as a generalization of variational inequalities. Their origin is in nonsmooth mechanics of solid, especially in nonmonotone contact problems. The solution of a hemivariational inequality proves to be a substationary point of some functional, and thus can be found by the nonsmooth and nonconvex optimization methods. We consider two type of bundle methods in order to solve hemivariational inequalities numerically: proximal bundle and bundle-Newton methods. Proximal bundle method is based on first order polyhedral approximation of the locally Lipschitz continuous objective function. To obtain better convergence rate bundle-Newton method contains also some second order information of the objective function in the form of approximate Hessian. Since the optimization problem arising in the hemivariational inequalities has a dominated quadratic part the second order method should be a good choice. The main question in the functioning of the methods is how remarkable is the advantage of the possible better convergence rate of bundle-Newton method when compared to the increased calculation demand.     

Microvascular permeability to macromolecules in human melanoma xenografts assessed by contrast-enhanced MRI--intertumor and intratumor heterogeneity.

Several novel macromolecular anticancer agents have fallen short of expectations owing to inadequate and heterogeneous uptake in tumor tissue. In the present work, contrast-enhanced magnetic resonance imaging was used to measure the intertumor and intratumor heterogeneity in the effective microvascular permeability constant, P(eff), of an 82 kDa macromolecule in an attempt to identify possible causes of the inadequate and heterogeneous uptake. Tumors of two human melanoma xenograft lines (A-07 and R-18) were included in the study. Human serum albumin with 30 gadopentetate dimeglumine units per molecule was used as a model molecule of macromolecular therapeutic agents. P(eff) was measured in manually defined regions of interest, corresponding to a whole tumor (ROI(WHOLE)) or to subregions of a tumor (ROIs(SUB)). The P(eff) of the ROI(WHOLE) of individual tumors ranged from 1.4 x 10(-7) cm/s to 2.8 x 10(-7) cm/s (A-07) and from 7.7 x 10(-8) cm/s to 3.2 x 10(-7) cm/s (R-18). P(eff) decreased with increasing tumor volume in R-18, but was independent of tumor volume in A-07. The intratumor heterogeneity in P(eff) exceeded the intertumor heterogeneity in both tumor lines. Some ROIs(SUB) showed P(eff) values that were similar to or slightly higher than the P(eff) values of albumin in normal tissues. Our observations suggest that inadequate and heterogeneous uptake of macromolecular therapeutic agents in tumor tissue is partly a result of low and heterogeneous microvascular permeability. However, the microvascular wall is probably not the major transport barrier to macromolecules in A-07 and R-18 tumors, as most individual tumors and individual tumor subregions showed high P(eff) values, i.e. values that are up to 10-fold higher than those of normal tissues.