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F14512 exploiting the polyamine transport system (PTS) for tumour cell delivery has been described as a potent antitumour agent. The optimal use of this compound will require a probe to identify tumour cells expressing a highly active PTS that might be more sensitive to the treatment. The aim of this study was to design and characterize a scintigraphic probe to evaluate its uptake in cancer cells expressing the PTS.Three polyamines coupled to a hydrazinonicotinamide (HYNIC) moiety were synthesized and labelled with 99mTc. Their radiochemical purity was determined by HPLC. The plasma stability of the 99mTc-HYNIC-spermine probe and its capacity to accumulate into PTS-active cells were also evaluated. In vitro internalization was tested using murine melanoma B16/F10 cells and human lung carcinoma A549 cells. Biodistribution was determined in healthy mice and tumour uptake was studied in B16/F10 tumour-bearing mice. A HL-60-Luc human leukaemia model was used to confront single photon emission computed tomography (SPECT) images obtained with the 99mTc-labelled probe with those obtained by bioluminescence.The 99mTc-HYNIC-spermine probe was selected for its capacity to accumulate into PTS-active cells and its stability in plasma. In vitro studies demonstrated that the probe was internalized in the cells via the PTS. In vivo measurements indicated a tumour to muscle scintigraphic ratio of 7.9±2.8. The combined bioluminescence and scintigraphic analyses with the leukaemia model demonstrated that the spermine conjugate accumulates into the tumour cells.The 99mTc-HYNIC-spermine scintigraphic probe is potentially useful to characterize the PTS activity of tumours. Additional work is needed to determine if this novel conjugate may be useful to analyse the PTS status of patients with solid tumours.

The authors unanimously wish to retract this Article due to their concerns about the interpretation of the low-energy electron microscopy (LEEM) and diffraction (LEED) patterns reported in the manuscript. In this study, the authors used spatial and angle-resolved photoemission spectroscopy (ARPES) to characterize graphene monolayers grown on copper foils, and observed regions of graphene adlayers with enhanced graphene/Cu interaction, higher Dirac cone doping level, moire mini Dirac cones and large lattice expansion. All these properties have been clearly verified and reproduced by photoemission spectroscopy as well as explained by density functional theory. LEEM and LEED characterization were also carried out to confirm the existence of a moire superlattice and lattice expansion, and the results were included in the main manuscript and Supplementary Information. On further analysis of the LEEM/LEED data, it seems that while the existence of a moire superlattice can be corroborated, the conclusion of graphene lattice expansion (7%) based on spatially resolved ARPES determinations cannot be confirmed by the LEEM/LEED measurements. The authors realized that these measurements were collected from statistically non-representative areas of the sample. Moreover, the fact that the raw microLEED images bear an asymmetry factor of as much as 5% due to the instrumental aberration makes it impossible to estimate any compression or expansion of the same order. Consequently, their conclusion on the graphene lattice expansion can only be supported by the photoemission data. In view that more complete and reliable structural determinations should be conducted, all authors wish to retract this Article.

Vinflunine, the most recent Vinca alkaloid in clinical development, demonstrated superior antitumour activity to other Vincas in preclinical tumour models. This study aimed to define its molecular mechanisms of cell killing in both parental sensitive and vinflunine-resistant P388 leukaemia cells. Vinflunine treatment of these cells resulted in apoptosis characterized by DNA fragmentation and proteolytic cleavage of poly-(ADP-ribose) polymerase. Apoptosis-inducing concentrations of vinflunine caused c-Jun N-terminal kinase 1 stimulation, as well as caspases-3/7 activation. This activation of caspases and the induction of apoptosis could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. Interestingly, the apoptosis signal triggered by vinflunine in these P388 cells was not mediated through Bcl-2 phosphorylation. In addition, when vinflunine resistance was developed in P388 cells, it was associated with resistance to vinflunine-induced apoptosis, as reflected by a loss of capacity to induce DNA fragmentation and PARP degradation, and characterized by increased levels of Bcl-2 and Bfl-1/A1. Therefore, these data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms. British Journal of Cancer (2002) 86, 143–150. DOI: 10.1038/sj/bjc/6600025 www.bjcancer.com © 2002 The Cancer Research Campaign

Purpose: Vinflunine (VFL) is a novel Vinca alkaloid with markedly superior experimental in vivo antitumour activity to its parent molecule, vinorelbine (Navelbine, NVB), against a panel of murine and human tumours. The aim of this study was to establish whether there are differences in the rate and extent of development of resistance, both in vivo and in vitro, to these two newer Vinca alkaloids under identical selection conditions. Methods: Using P388 leukaemia cells in vivo, it was evident that VFL induced drug resistance far less readily than NVB, as shown by the number of passages required to select for total resistance. Under in vitro conditions, using A549 human lung carcinoma cells, it was also clearly shown by drug sensitivity determinations that VFL was a less-potent inducer of drug resistance than NVB. Resistance resulting from either in vivo or in vitro selection was associated with a classic multidrug resistance profile. Further characterization of the drug-resistance phenotype of the most highly resistant A549 sublines showed that the level of total β-tubulin expression appeared to be modified exclusively in the NVB-resistant cells. Conclusion: The clear demonstration that resistance to VFL developed far less readily than resistance to NVB both in vivo and in vitro may have potential clinical implications.

Vinflunine, or 20',20'-difluoro-3',4'-dihydrovinorelbine, is a novel Vinca alkaloid obtained by hemisynthesis using superacidic chemistry. The most impressive structural modification of this vinorelbine derivative was the selective introduction of two fluorine atoms at the 20' position, a part of the molecule previously inaccessible by classic chemistry. The antitumor activity of vinflunine was evaluated against a range of transplantable murine and human tumors. Vinflunine exhibited marked activity against murine P388 leukemia grafted i.v. when given i.p. in single or multiple doses according to various schedules or in single i.v. or p.o. doses. Increases in life span achieved with vinflunine, as assessed by T/C ratios, ranged from 200% to 457% and proved markedly superior to those of 129-186% obtained with the other Vinca alkaloids tested. Against s.c.-implanted B16 melanoma, multiple i.p. administration of vinflunine proved active in terms of both survival prolongation and tumor growth inhibition, with optimal T/C values and relative areas under the tumor growth curves (rAUC) being 24% and 36%, respectively. The extent of this activity was superior to that noted for vinorelbine under the same experimental conditions. Growth inhibition of human tumor xenografts LX-1 (lung) and MX-1 (breast) was also observed following four weekly i.p. injections of vinflunine as reflected by optimal T/C values of 23% and 26%, respectively, and significant differences in the rAUCs noted for treated versus control animals. It was also noticeable that vinflunine induced considerably more prolonged inhibitory effects on tumor growth than did vinorelbine. These results demonstrate that vinflunine is well tolerated and is definitively active against a range of experimental animal tumor models. Vinflunine activity has been documented in terms of both survival prolongation and tumor growth inhibition, with definite superiority over vinorelbine being shown in each tumor model evaluated.

Seasonal patterns (i.e., December 1986, and April and October 1987) in benthic macroinfaunal abundance,distribution, and taxa composition at 19 sites in Perdido Bay, AL/FL, are evaluated to assess the relative importance of environmental factors as determinants of community structure. A total of 46 taxa from five phyla were collected with diver-held bottom corers. Polychaetes were numerically dominant followed by crustaceans. Seventeen taxa co-occurred in samples during all three study periods. Maximum animal densities and taxa richness showed no statistically significant bay-wide seasonal pattern,however, a bay-wide trend was detected where these response parameters tended to be greater in April than December or October. Deeper upper bay stations were depauperate during December and October. Low dissolved oxygen (DO) largely explained the depauperate pattern. Mean taxa richness per core(10 cm dia.) ranged from 0.0 to 5.0, 1.2 to 4.6, and0.0 to 4.4 in December, April and October,respectively. Mean densities ranged from zero to 368,0 to 960, and 0 to 430 individuals per 0.1 m2 in December, April, and October, respectively. Results of a three-season statistical regression model indicated that DO deficiency was a primary determinant of taxa richness (partial R 2: 0.27) but was less important in explaining animal densities (partialR 2: 0.16). For December, when additional environmental variables were measured, DO was supplanted by weight loss on ignition (R 2: 0.24)and the sediment C:N ratio (R 2: 0.44) as highest explanatory factors for taxa richness and density,respectively. Application of a benthic index of environmental condition indicated wide-spread ecological stress on the benthic macroinfaunal assemblages.

To review a series of critically ill obstetric patients admitted to a general intensive care unit in a Canadian centre, to assess the spectrum of diseases, interventions required and outcome.A retrospective chart review was performed of obstetric patients admitted to the intensive care unit of an academic hospital with a high-risk obstetric service, during a five-year period. Data obtained included the admission diagnosis, ICU course and outcome. Daily APACHE II and TISS scores were recorded.Sixty-five obstetric patients, representing 0.26% of deliveries in this hospital, were admitted to the ICU during the study period. All had received prenatal care. Admission diagnoses included obstetric (71%) and non-obstetric (29%) complications. The mean APACHE II score was 6.8 +/- 4.2 and mean TISS score was 24 +/- 8.1. Twenty-seven patients (42%) required mechanical ventilation. No maternal mortality occurred and the perinatal mortality rate was 11%.A small proportion of obstetric patients develop complications requiring ICU admission. The outcome in this study was excellent, in contrast to that reported in other published studies with similar ICU admission rates. The universal availability of prenatal care may be an important factor in the outcome of this group of patients. The lack of a specific severity of illness scoring system for the pregnant patient makes comparison of case series difficult.

The influence of five anti-hormone and/or anti-growth factor neutralizing antibodies on the in vitro proliferation of four human astrocytic tumor cell lines (U87, U138, U373, H4) is quantitatively described by means of a new tool which makes it possible to evaluate cell growth and cell clone architecture concomitantly. This tool relies upon the combined use of the digital cell image analyses of Feulgen-stained nuclei and the Delaunay and Voronoi mathematical triangulation and paving techniques. Of the five anti-hormone and/or anti-growth factors tested here, the anti-luteinizing hormone-releasing hormone (LHRH) antibody induced the most marked perturbation in the U138 and U373 cell lines, whereas this role was played by the anti-epidermal growth factor (EGF) antibody in the U87 and H4 cell lines. The anti-gastrin (G) antibody significantly modified the growth and/or cell clone architecture of the U138, U87 and H4 cell lines, as did the anti-transforming growth factor alpha (TGFalpha) antibody. The anti-transforming growth factor beta (TGFbeta) antibody modified the growth and/or cell clone architecture of the four cell lines under study. If the five antibodies are taken into consideration, the results strongly suggest that four (the anti-G, the anti-EGF, the anti-LHRH and the anti-TGFalpha) act as inhibitory agents on some glioma cell line proliferation, while the fifth one, i.e. the anti-TGFbeta, act as a stimulator of cell proliferation, perhaps by abrogating the inhibitory effects of TGFbeta on proliferation. A comparison of cell growth data with cell clone architecture characteristics provided further evidence of some specific influence exercised by a given hormone and/or growth factor on glioma cell proliferation. Indeed, the anti-LHRH antibody caused the most pronounced perturbations in the U138 and U373 cell clone architecture; this feature was observed in the H4 cell line and, to a lesser extent in the U87 one after the anti-EGF antibody had been used.

The rutile modification of TiO2 in the form of a powder suspended in water shows promise as a photocatalyst for the production of hydrogen from water1,2. Although hydrogen production was reported3 from pure rutile powder suspended in an aqueous solution, subsequent work1,2 revealed that sustained hydrogen production required Pt or RuO2 on the rutile surface. This limiting usefulness of crystalline rutile in photocatalytic applications has prompted us to investigate the photocatalytic properties of amorphous titania in the form of a porous glass. Here we report an inexpensive method of forming monolithic porous titania glass (PTG) and some properties that make it uniquely suited to photocatalytic applications such as its inexpensive fabrication, its high surface area, and its spontaneous photo-formation of H2 from water without the need for precious metals.

Blue mussels,Mytilus edulis, were collected from eight sites near Woods Hole, Massachusetts and examined for presence of the symbiont,Pinnotheres maculatus. Mussels (550) from 6 intertidal areas contained 2 crabs. Mussels (421) from 2 subtidal areas contained 238 crabs. Only 1% of mussels growing near the surface on a piling contained crabs, while those from depths of 10 feet and below were highly infected.

Cyathura polita was the most common infaunal macroinvertebrate in a north FloridaJuncus roemerianus marsh. Density was 58 and 75/m2 in lower and upper marsh zones, respectively, during a 19 month study period. It was randomly distributed in both marsh zones, but density was greatest 200 m from low water. Population analysis indicated that reproduction occurred in April, young were common in May and these produced young the following April. Males matured first, and there was some evidence for possible protogynous hermaphroditism. Smaller body size, shorter maturation period and a different environment from previously reported populations ofC. polita suggest that we have described a new ecotype located in a distinctively different biotope.

Bay scallops containing adult female pea crabs are slightly smaller than noninfected scallops. Infected scallops tend to weigh less than noninfected of the same size. The growth of 3 size groups of infected and noninfected scallops was measured over a 3 month period and infected scallops grew less than noninfected.