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The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is epigenetically silenced in some tumors by MGMT gene promoter methylation. MGMT-hypermethylated solid tumors have enhanced susceptibility to the cytotoxic effects of alkylating chemotherapy such as temozolomide, compared with non-methylated tumors. In glioblastoma, subjects with MGMT hypermethylation have significantly longer survival rates after chemoradiotherapy. We report the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified anti-MGMT morpholino oligonucleotide (AMON) sequences. We demonstrate >40% reduction in the in vitro proliferation index and cell viability in radiation-primed MGMT-expressing human solid tumor cells treated with a single dose of AMONs and temozolomide. We further demonstrate the feasibility of using a non-ablative dose of radiation in vivo to guide and enhance the delivery of intravenously administered AMONs to achieve 50% MGMT knockdown only at radiation-primed tumor sites in a subcutaneous tumor model. Local upregulation of physiological endocytosis after radiation may have a role in radiation-guided uptake of AMONs. This approach holds direct translational significance in glioblastoma and brain metastases where radiation is part of the standard of care; our approach to silence MGMT could overcome the significant problem of MGMT-mediated chemoresistance.

As part of its ongoing project on repositories for high-activity, long-lived radioactive waste, a 2000 m deep borehole was drilled by the French Nuclear Waste Agency (ANDRA) in the layered structure of alternating aquifers and aquitards of the Eastern Paris Basin. Among the information retrieved from this borehole, the vertical distribution of chloride in porewaters showed that, in addition to vertical diffusion, lateral advection in the aquifers plays a major part in transporting chlorine away from the study area. Helium concentrations were also measured in porewaters along the borehole. Because the helium input function is different from that of chlorine, it represents an excellent alternative tracer to further constrain transport characteristics. We applied an advection–diffusion model to the helium profiles with the appropriate source term for 4He based on U–Th measured concentrations of uranium and thorium. 40Ar/36Ar data, which were available along the whole sequence, were also simulated. The modelled and measured 4He profiles were in good agreement, indicating that the transport parameters used for the chlorine simulations were robust. 40Ar/36Ar simulations also gave coherent results and confirmed that most of the radiogenic 40Ar remained trapped in the rocks (primarily in clays and feldspars).

From the reactions between 2,2‘-ethylidenebis(4,6-di-tert-butylphenol) and 2,2‘-methylidenebis(4-dimethyl-6-di-tert-butylphenol) and Et2AlCl the biphenoxide complexes [(O~~CHMe~~O)AlCl]2, 1, and [(O~~CH2~~O)AlCl]2, 2, have been isolated and characterized. These dimers are broken up by donor ligands, and the molecular structure of ethylidenebis(4,6-di-tert-butylphenoxide)AlCl(THF), 3, has been structurally characterized. Racemic 5,5‘-6,6‘-tetramethyl-3,3‘-di-tert-butyl-1,1‘-biphen-2,2‘-diol and Et2AlCl react in hexane to give [(O~~O)AlCl]2, compound 6, as a hydrocarbon insoluble white precipitate. In the donor solvent THF monomeric species are formed, and (O~~O)AlX(THF) has been crystallographically characterized, X = 20% Cl and 80% Et occupancy. Refluxing in THF favors X = Cl, compound 4. The reaction of Et2Al(OEt) with the biphenol gives (O~~O)AlEt(THF), 5, in the presence of THF by displacement of one ethyl and one ethoxide ligand. Compounds 1, 2, 3, 4, 5, 6, [(O~~CHMe~~O)Al(OⁱPr-d7)]2, and [Cp2Zr(OEt)(OEt2)]⁺[HB(C6F5)3]^- act as propylene oxide, PO, polymerization catalyst precursors. The polymers have been examined by MS techniques and NMR spectroscopy, and these results are compared with polypropylene oxide, PPO, formed by base catalysis and by porphyrin- and salen-AlCl catalyst precursors. The new Al compounds and the cationic zirconium alkoxide give close to 50:50 HH to TT junctions with end groups C−Cl, OH, and =CH2 being identified by MS and NMR. Polymerizations employing [(O~~CHMe~~O)Al(OⁱPr-d7)]2 give HO−(PO)n−OⁱPr-d7 oligomers, in addition to vinyl-terminated species. Polymerization of S-PO and 50:50 mixtures of S-PO and rac-PO reveals that the stereoirregular polymer is formed by a stereoselective ring-opening step. An analysis of the HH and TT junctions at the triad level is made, extending the earlier assignments of Tonelli and Schilling. This analysis leads us to suggest that polymerization occurs by a cationic coordinate mechanism wherein ring opening occurs by backside attack on an activated PO molecule which leads to inversion at the methine carbon. The rac-biphenoxide−Al complexes show a preference for ii and i linkages in (HT)(HT)(HT) units. These results are compared to coordinate catalysis polymerizations of PO employing the Union Carbide calcium amide−alkoxide system and (porphyrin)AlCl and lead us to predict that a cis-migratory ring-opening polymerization process is not likely to be developed for polymerization of PO.

A mineralogical, petrological and chemical study on samples issued from drill core MAR 501 documents the diagenetic evolution of Upper Cretaceous siltstones at the western margin of the South-Eastern French basin. The main detrital grains (quartz, feldspars, muscovite, ilmenite), bioclasts and organic matter are partly altered by carbonate fluids, liberating Si, Ba, K, Ca, Mg, Sr, Fe, S, P and Ti. Early diagenetic glauconite incorporated Fe and K. During burial, glauconite is transformed into clay minerals with liberation of Fe and K. The diagenetic fluids precipitated framboidal pyrite, Ti oxides in clay filled cataclastic fissures of glauconite, collophane which traps P and F and part of the S in its structure and precipitation of the excess S as Fe-sulphides. Zircon, rutile and tourmaline were not altered. Quartz overgrowth around detrital quartz grains was rarely observed. Two major types of calcite are present. Large Fe-rich calcite II replaced Fe-poor micritic calcite I. Minor dolomite, Fe-dolomite and Sr-bearing baryte were contemporaneous to calcite II. Calcite II of poikilotopic texture embedded detrital quartz and formed scattered centimetric patches leading to a heterogeneous porosity along the drill core.

Phylogenies of organisms are essential to investigating a range of evolutionary questions of interest to researchers in the field of bioinformatics. Phylogenies not only help to define how to study many evolutionary questions, they must also be taken into account when conducting statistical analyses. Here it is shown how phylogenies can be used to investigate variability along the sites of a gene, reconstruct ancestral states of ancient genes and proteins, identify and characterise events of parallel and convergent evolution, find events of gene duplication, analyse predictions from molecular clocks, seek evidence for correlated changes among different parts of the same gene or genome, and test theories of molecular evolution. A table of statistical and phylogenetic methods is presented.

Fluid inclusions have been observed and studied in rocks of most types of uranium deposits, except surficial ones such as calcretes and the roll-type in sandstone. Temperatures of formation range up to nearly 400°C but most deposits were formed at more moderate temperatures of 90-250°C. It is evident from the relatively small number of studies, however, that the ore-forming process occurred at deeper levels than previously thought.
The chemistry of the fluids ranges from nearly pure water to very dense brines and CO₂ is a common component. In some cases gas analyses allow determination of f_o2 of the fluid, a key parameter for uranium transport and deposition.

The delivery of viral vectors to the brain for treatment of intracerebral tumors is most commonly accomplished by stereotaxic inoculation directly into the tumor. However, the small volume of distribution by inoculation may limit the efficacy of viral therapy of large or disseminated tumors. We have investigated mechanisms to increase vector delivery to intracerebral xenografts of human LX-1 small-cell lung carcinoma tumors in the nude rat. The distribution of Escherichia coli lacZ transgene expression from primary viral infection was assessed after delivery of recombinant virus by intratumor inoculation or intracarotid infusion with or without osmotic disruption of the blood-brain barrier (BBB). These studies used replication-compromised herpes simplex virus type 1 (HSV; vector RH105) and replication-defective adenovirus (AdRSVlacZ), which represent two of the most commonly proposed viral vectors for tumor therapy. Transvascular delivery of both viruses to intracerebral tumor was demonstrated when administered intraarterially (i.a.) after osmotic BBB disruption (n = 9 for adenovirus; n = 7 for HSV), while no virus infection was apparent after i.a. administration without BBB modification (n = 8 for adenovirus; n = 4 for HSV). The thymidine kinase-negative HSV vector infected clumps of tumor cells as a result of its ability to replicate selectively in dividing cells. Osmotic BBB disruption in combination with i.a. administration of viral vectors may offer a method of global delivery to treat disseminated brain tumors.

Zusammenfassung Die thermal bedingte Entwicklung permischer Schichten in der »Breccia Pipes« Region der Colorado-Hochebene wurde mittels dreier Geothermometer rekonstruiert. Die Rekonstruktion der Ablagerungsgeschichte deutet auf maximale Temperaturen zwischen 100 ° und 140 °C hin. Eine Spaltspuren-Analyse erbrachte als Ergebnis eine maximale Temperatur von 137 °C, die über 50 Ma. integriert wurde. Diese Ergebnisse stimmen mit der Minimum-Temperatur überein, die mit Hilfe von Flüssigkeitseinschlüssen (75°–140 °C) errechnet wurden. Die Hypothesen der Spaltspuren-Analyse und der Ablagerungsgeschichte wurden in ein kinetisches Modell der Reifung von organischen Substanzen miteinbezogen. Die errechneten Durchschnitts-temperaturen liegen bei 445° und 421 °C. Ein Vergleich mit Daten der organischen Geochemie aus der permischen »Toroweap« Formation zeigt, daß die zwei oben genannten Hypothesen es erlauben, thermale Rahmenbedingungen für die Entwicklung organischer Substanzen festzusetzen. Die wichtigsten Schlüsse, die aus dieser Studie gezogen werden können sind das Alter des Beginns der Ölbildungsphase und der regionalen Hebungsphase (Laramid-Orogenese) sowie die Spannweite der maximalen Temperaturen.

Sodium thiosulfate (STS) provides protection against carboplatin-induced ototoxicity in an animal model. The purpose of this study was to determine the STS dose required for otoprotection, in patients with malignant brain tumors treated with carboplatin in conjunction with osmotic blood-brain barrier disruption. Twenty-nine patients received STS intravenously 2 hr after carboplatin. Doses were escalated from 4 g/m2 to 8, 12, 16 and 20 g/m2 on consecutive months. Audiologic assessment was performed at baseline and monthly. The audiograms were compared with those of 19 similarly treated historical control patients who did not receive STS. The incidence of ototoxicity in the historical control group of patients was 79% (15/19). This group had an average loss of 20.8 +/- 5.9 dB (n = 19) at 8 kHz after one treatment with carboplatin, whereas the STS treatment group lost only 3.7 +/- 2 dB (n = 15) after one treatment. This difference was statistically significant as assessed by Student's t test (P < .05). Furthermore, patients in the STS treatment group with excellent base-line hearing showed little change in hearing thresholds at 8 kHz after the second treatment (8.0 +/- 8.3 dB) (n = 5) compared with the historical control patients with excellent base-line hearing, (40.5 +/- 8.6 dB) (n = 11). Our data support that doses of 16 or 20 g/m2 of STS decrease carboplatin-induced hearing loss without central nervous system entry. Clinical demonstration of an otoprotective effect with a two-compartment system to prevent drug-induced hearing loss, while preserving central nervous system cytotoxicity, has not been reported previously.

We report the synthesis and ¹H, ¹³C{¹H}, and phase-sensitive HETCOR NMR spectra of atactic poly(lactide), poly(meso-lactide) and poly(rac-lactide). The new and existing spectroscopic data are discussed in terms of four alternative explanations:  (i) Kricheldorf's tetrad assignments with the presumption that the adjacent chiral units exert an asymmetric influence on chemical shifts which is propagated in opposite directions along the polymer chain for ¹H and ¹³C nuclei, respectively, (ii) alternative tetrad assignments we have recently proposed, (iii) assignments based on pentad stereosequences, and (iv) assignments based on the observation of triad and pentad stereosequences rather than tetrads. We show that the available data are insufficient to unequivocally distinguish between explanations i or iv.

Among the various reactions of lipid peroxidation products with proteins, 2-alkenals have been shown to react extensively with the ε-amino group of lysine residues [Žídek et al. (1997) Chem. Res. Toxicol. 10, 702−710]. To obtain additional information about the kinetic and mechanistic aspects of this modification, a model peptide (N-acetylglycyllysine O-methyl ester) was reacted with 2-hexenal. The reaction products were characterized through a combination of NMR and MS techniques. The structural elucidation efforts have shown the formation of pyridinium salts through the reaction of two or more alkenals with one amino group. Kinetic data were obtained using a continuous infusion of the reaction mixture into an electrospray ionization mass spectrometer. A mechanism is proposed that offers an alternative model for the formation of stable protein cross-links. The reaction progresses through a Schiff base intermediate to form a dihydropyridine species which can be alternatively reduced to form various 3,4- or 2,5-substituted pyridinium species or react with another Schiff base to form a trialkyl-substituted pyridinium structure. The stoichiometry of this structure (aldehyde/amine) is 3:2, in contrast to the widely accepted 1:2. Therefore, it represents another possible cross-linking mechanism for bifunctional products of lipid peroxidation.

Abstract: A La-Ce-Sr-Ca aluminous hydroxy phosphate of the goyazite-florencite-crandallite series was observed in the nuclear reactor zone 13 in the Oklo uranium deposit (Gabon). It has a trigonal elementary cell with a = 6.98 0.03 and c = 16.35  0.04  (space group P3m). It occurs in a U-rich sample depleted in 235U (235U/238U = 0.0047). Its chemical composition, measured by ion microprobe analyses, shows that it contains fission products (Zr, LREE) whereas the isotopic composition of Ba and Sr is natural. Ion microprobe imaging indicates that the nearby uraninite crystals are depleted in fissiogenic LREE. This study shows that the migration of some fission products, probably related to a dolerite dike intrusion, is limited by the formation of aluminous hydroxy phosphates.

Infrared spectra of fluid inclusions are obtained with a Fourier transform infrared miscrospectrometer. The experimental conditions and the analytical use are discussed. Interferograms are recorded in the transmission mode. The quality of spectra is good for fluid inclusions with diameters larger than 30 μm, the spectral resolution being 4 cm−1and the recording time 200 s. Interferograms made of inclusions with diameters of less than 20 μm are reached in the same amount of time, but with worse spectral resolution. Infrared spectra are usually only suitable above 2000 cm−1, because of the absorption of most of the inclusion-bearing host minerals, the thickness of which should never exceed 1 mm. This fact further limits their interpretation, as the inclusion composition is complex. However, complementary information can be obtained in the 4600–4000-cm−1range for hydrocarbon inclusions with a thickness that is larger than some tens of micrometers. This shows that it is necessary to use a detector which is as sensitive as possible towards high frequencies. A comparison of the current performances of infrared and Raman spectroscopies as analytical methods for investigating fluid inclusions is presented. The important improvement of better spatial resolution and the corresponding possibility of being able to characterize heterogeneities, in comparison to limitations with classical dispersive infrared spectrometry, are discussed. Methane, carbon dioxide, liquid water, aromatic ester, and linear or branched alkanes are identified in several samples. It is also possible to estimate the mean ratio of alkane CH2/CH3groups. In some cases, the intensity of the absorptions indicates the inclusion effective thickness and the mole fraction ratio.

The present studies were undertaken to evaluate the possibility that hexosaminidase A, the enzyme deficient in Tay--Sachs disease, could be effectively delivered to brain. Previous studies from our laboratory have shown that hypertonic mannitol can be used to osmotically produce reversible disruption of the blood--brain barrier in animals (rat and dog) and man without significant neurotoxicity and that such barrier modification significantly increases the delivery of cytoreductive chemotherapy agents to selected areas of brain. By using the rat model of blood--brain barrier modification and radiolabeled enzyme, increased hexosaminidase A delivery to brain has been demonstrated in more than 85 animals. The time of injection of hexosaminidase A after blood--brain barrier disruption is critical for maximum delivery. Rapid (over 30 sec) intra-arterial administration of hexosaminidase A immediately after blood--brain barrier disruption resulted in a marked increase in enzyme delivery to the brain when compared with controls without prior barrier disruption. When the enzyme was administered 15-20 min after barrier disruption, approximately 50% less hexosaminidase A was delivered; when given 60-120 min after barrier modification, the amount delivered was the same as in control animals. This critical time course is very different than that seen in trials of low molecular weight chemotherapeutic agents (methotrexate and adriamycin). These preliminary studies suggest that hexosaminidase A can be delivered to the brain by blood--brain barrier modification and may be indicative of the potential for enzyme replacement in patients who hae Tay--Sachs disease.

The use of 2D homonuclear J-resolved ¹H NMR spectroscopy in the examination of the methine region of poly(cyclohexene oxide) formed by polymerization of cyclohexene oxide employing the Union Carbide calcium−amide−alkoxide catalyst reveals that the majority of the ring opening occurs by backside attack.

When bacteriophage SP02 infects a Bacillus subtilisculture during or shortly after transformation, the frequency of transformants among the resulting lysogens is greatly reduced relative to that in the uninfected culture. The effect can occur after the deoxyribonucleic acid has been taken up and covalently attached to recipient deoxyribonucleic acid.

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