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PURPOSE To evaluate health care systems for the availability of population-level data on the frequency of use and results of clinical molecular marker tests to inform precision cancer care. METHODS We assessed cancer-related molecular marker test data availability across 12 US health care systems in the Cancer Research Network. Overall, these systems provide care to a diverse population of more than 12 million people in the United States. We performed qualitative analyses of test data availability for five blood-based protein, nine germline, and 14 tissue-based tumor marker tests in each health care system’s electronic health record and tumor registry using key informants, test code lists, and manual review of data types and output. We then performed quantitative analyses to estimate the proportion of patients with cancer with test utilization data and results for specific molecular marker tests. RESULTS Health systems were able to systematically capture population-level data on all five blood protein markers, six of 14 tissue-based tumor markers, and none of the nine germline markers. Successful, systematic data capture was achievable for tests with electronic data feeds for test results (blood protein markers) or through prior manual abstraction by tumor registrars (select tumor-based markers). For test results stored in scanned image files (particularly germline and tumor marker tests), information on which test was performed and test results was not readily accessible in an electronic format. CONCLUSION Even in health care systems with sophisticated electronic health records, there were few codified data elements available for evaluating precision cancer medicine test use and results at the population level. Health care organizations should establish standards for electronic reporting of precision medicine tests to expedite cancer research and facilitate the implementation of precision medicine approaches.

Summary Background Artemisinin-based combination therapies (ACTs) are the recommended first-line treatment for uncomplicated Plasmodium falciparum malaria. Ferroquine is a new combination partner for fast-acting ACTs such as artesunate. We aimed to assess different doses of ferroquine in combination with artesunate against uncomplicated P falciparum malaria in a heterogeneous population in Africa. Methods We did a phase 2, multicentre, parallel-group, double-blind, randomised, dose-ranging non-inferiority trial at eight African hospitals (two in Gabon, three in Burkina Faso, one in Benin, and two in Kenya). We recruited patients presenting with acute P falciparum monoinfection (1000–200 000 parasites per μL), and a central body temperature of at least 37·5°C or history of fever in the past 24 h. We assessed patients in two sequential cohorts: cohort 1 contained adults (bodyweight >50 kg) and adolescents (aged ≥14 years, >30 kg), and cohort 2 contained children (aged 2–13 years, 15–30 kg). We randomly assigned patients (1:1:1:1) to receive artesunate 4 mg/kg per day plus ferroquine 2 mg/kg, 4 mg/kg, or 6 mg/kg, given double-blind once per day for 3 days, or ferroquine monotherapy 4 mg/kg per day given single-blind (ie, allocation was only masked from the patient) once per day for 3 days. We did 14 patient visits (screening, 3 treatment days and 48 h post-treatment surveillance, a visit on day 7, then one follow-up visit per week until day 63). The primary endpoint was non-inferiority of treatment in terms of PCR-corrected cure rate against a reference value of 90%, with a 10% non-inferiority margin, assessed in patients treated without major protocol deviations for parasitologically confirmed malaria. We assessed safety in all treated patients. This study is registered with ClinicalTrials.gov, number NCT00988507, and is closed. Findings Between Oct 16, 2009, and Sept 22, 2010, we randomly assigned 326 eligible patients to treatment groups, with last follow-up visit on Dec 1, 2010. 284 patients (87%) were available for per-protocol analyses. At day 28, PCR-confirmed cure was noted in 68 (97%, 95% CI 90–100) of 70 patients treated with ferroquine 2 mg/kg plus artesunate, 73 (99%, 93–100) of 74 with ferroquine 4 mg/kg plus artesunate, 71 (99%, 93–100) of 72 with ferroquine 6 mg/kg plus artesunate, and 54 (79%, 68–88) of 68 with ferroquine 4 mg/kg monotherapy. The three dose groups of ferroquine plus artesunate met the non-inferiority hypothesis. The most common adverse events were headache in cohort 1 (30 [19%] of 162 patients) and worsening malaria in cohort 2 (23 [14%] of 164 patients); occurrences were similar between treatment groups. Interpretation Ferroquine combined with artesunate was associated with high cure rates and was safe at all doses tested, and could be a promising new drug combination for the treatment of P falciparum malaria. Ferroquine could also partner other drugs to establish a new generation of antimalarial combinations, especially in regions that have developed resistance to ACTs. Funding Sanofi.

Ferroquine (SSR97193), a ferrocene-quinoline conjugate, is a promising novel antimalarial currently undergoing clinical evaluation. This study characterizes its pharmacokinetic properties. Young male African volunteers with asymptomatic Plasmodium falciparum infection were administered a single oral dose ( n = 40) or a repeated oral dose ( n = 26) given over 3 days of ferroquine in two dose-escalation, double-blind, randomized, placebo-controlled clinical trials. In addition, a food interaction study was performed in a subsample of participants ( n = 16). The studies were carried out in Lambaréné, Gabon. After single-dose administration of ferroquine, dose linearity was demonstrated in a dose range of 400 to 1,200 mg for maximum mean blood concentrations ([ C max ] 82 to 270 ng/ml) and in a dose range of 400 to 1,600 mg for overall exposure to ferroquine (area under the concentration-time curve [AUC], 13,100 to 49,200 ng · h/ml). Overall mean estimate for blood apparent terminal half-life of ferroquine was 16 days and 31 days for its active and major metabolite desmethylferroquine (SSR97213). In the 3-day repeated-dose study, C max and overall cumulated exposure to ferroquine (AUC cum ) increased in proportion with the dose from day 1 to day 3 between 400 and 800 mg. No major food effect on ferroquine pharmacokinetics was observed after single administration of 100 mg of ferroquine except for a slight delay of time to maximum blood concentration ( t max ) by approximately 3 h. The pharmacokinetics of ferroquine and its active main metabolite are characterized by sustained levels in blood, and the properties of ferroquine as a partner drug in antimalarial combination therapy should be evaluated.

Surfaces of thin low-density polyethylene films are chemically modified either by oxidation or by grafting with maleic acid. The oxidation is performed at constant tempera-ture by sulfuric acid and potassium chlorate mixtures of variable compositions. Grafting was carried out at constant temperature and time in the solution of maleic anhydride in acetic anhydride in the presence of benzoyl peroxide initiator. Isotherms of calcium adsorption at these surfaces have been established by the use of the radioactive tracer technique. The chemical composition (number of obtained polar sites) of these modified polyethylene surfaces is thus determined. The measurements were conducted at different pH and salt concentrations. Wettability of the modified surfaces is determined by contact angle measurements. It was found that the wettability of these films is directly related to the chemical composition of their surfaces.

The influence of ethanol on protein (e.g., bovine serum albumine (BSA)) adsorption from aqueous solutions has been investigated by surface tensiometry. The surface reaches a quasi-equilibrium state resulting from the competitive adsorption of ethanol and BSA molecules. At less than 5%, v/v, ethanol content, kinetics of surface pressure increase results from the combination of two processes: a fast migration and adsorption that may be enhanced by a change in the state of BSA molecules in bulk solution (e.g., self-assembling), and a slow increase of surface pressure possibly caused by protein unfolding at the surface. These experiments made it possible to define a degree of BSA molecules unfolding. At 12%, v/v, ethanol content, the surface pressure kinetics display an overshoot effect. This effect results from the superposition of three processes: a very fast adsorption of BSA molecules, an irreversible desorption of some adsorbed BSA, and unfolding of the remaining BSA molecules.

Urinary metabolites of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, termed total NNAL, have recently been shown to be good predictors of lung cancer risk, years before diagnosis. We sought to determine the contribution of several genetic polymorphisms to total NNAL output and inter-individual variability. The study subjects were derived from the Harvard/Massachusetts General Hospital Lung cancer case-control study. We analyzed 87 self-described smokers (35 lung cancer cases and 52 controls), with urine samples collected at time of diagnosis (1992-1996). We tested 82 tagging SNPs in 16 genes related to the metabolism of NNK to total NNAL. Using weighted case status least squares regression, we tested for the association of each SNP with square-root (sqrt) transformed total NNAL (pmol per mg creatinine), controlling for age, sex, sqrt packyears and sqrt nicotine (ng per mg creatinine). After a sqrt transformation, nicotine significantly predicted a 0.018 (0.014, 0.023) pmol/mg creatinine unit increase in total NNAL for every ng/mg creatinine increase in nicotine at p < 10E-16. Three HSD11B1 SNPs and AKR1C4 rs7083869 were significantly associated with decreasing total NNAL levels: HSD11B1 rs2235543 (p = 4.84E-08) and rs3753519 (p = 0.0017) passed multiple testing adjustment at FDR q = 1.13E-05 and 0.07 respectively, AKR1C4 rs7083869 (p = 0.019) did not, FDR q = 0.51. HSD11B1 and AKR1C4 enzymes are carbonyl reductases directly involved in the single step reduction of NNK to NNAL. The HSD11B1 SNPs may be correlated with the functional variant rs13306401 and the AKR1C4 SNP is correlated with the enzyme activity reducing variant rs17134592, L311V.

Introduction: Tobacco-specific nitrosamine (TSNA) NNK metabolites NNAL and NNAL-gluc) together, (total NNAL), have recently been shown to be good predictors of lung cancer risk, years prior to diagnosis. However, the inter-individual variability in the metabolism of NNK evaluated by the total NNAL output could be explained in part by genetic variability in the genes of NNK metabolism. We sought to determine the contribution of several genetic polymorphisms to total NNAL output by a regression analysis of NNAL levels on genotyping results, controlling for measures of smoking, age and sex. Methods: The study subjects were derived from the Harvard/ Massachusetts General Hospital Lung cancer case-control study. We selected 92 subjects (39 lung cancer cases and 53 controls) smokers at time of diagnosis and urine collection (1992-1996). We tested 77 tagging SNPs in 16 genes related to NNK to NNAL metabolism. Using case status as a mediator, we tested for the association of each SNP with square-root (sqrt) transformed NNAL (pmol per mg creatinine), controlling for age, sex, sqrt packyears and sqrt nicotine (ng per mg creatinine). Results: After a sqrt transformation, nicotine significantly predicted a 0.02 (0.015, 0.023) pmol/mg creatinine unit increase in NNAL for every ng/mg creatinine increase in nicotine at p = 2.85E-12. Three HSD11B1 SNPs, located in a 14kb region flanked by rs2235543 and rs3753519 in intron 1, were significantly associated with decreasing NNAL levels. Two of these SNPs, rs2235543 (p = 4.84E-08) and rs3753519 (p = 0.0017), passed multiple testing correction at FDR q value=1.07E-05 and 0.06 respectively. AKR1C4 rs7083869 G>A was also to be significantly associated with decreasing NNAL levels, p=0.019, FDR q=0.48. Conclusions: HSD11B1 and AKR1C4 enzymes are carbonyl reductases directly involved in the single step reduction of NNK to NNAL. The HSD11B1 SNPs may be correlated with the functional variant rs13306401 and the AKR1C4 SNP correlated with the enzyme activity reducing variant rs17134592, L311V. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2758. doi:10.1158/1538-7445.AM2011-2758

Mesures de dilatation et de compressibilite de 200 a 450 K jusqu'a 4 kbar. On observe une anomalie dans les capacites calorifiques a basse temperature et haute densite

The surface potential ΔV of monolayers of a hydrophobic polyacid HPA, the alternate copolymer of maleic acid and of hexadecylvinylether, spread at the surface of aqueous solutions, has been studied as a function of pH, ionic strength, and Ca2+ concentration. In the absence of Ca2+ ions, the ΔV—pH plots resemble acid—base titrations curves, and ΔV is practically independent of the ionic strength. In the presence of Ca2+ ions, ΔV increases slightly when the amount of bound Ca2+ ions is increased by varying either the bulk ratio Ca2+/Na+ or the bulk pH. It is assumed that the majority of the counterions Na+ or Ca2+ is paired to the carboxylates of the dissociated HPA and that the contribution to ΔV of the diffuse part of the double layer is negligible. Then, the variation of the degree of dissociation and the pK of the maleic acid residues of HPA are deduced in the absence of Ca2+ ions. It is found that only one carboxyl group of the maleic acid residue is dissociated when the bulk pH An analogous increase of the surface charge density of the monolayers follows the exchange Ca2+/Na+ owing to the replacement of one Na+ by one Ca2+. This “charging” of the surface seems to be responsible of the increase in ΔV. Furthermore, in this case, and when the amount of bound Ca2+ ions is high, the presence of positively charged sites next to the second undissociated carboxyl group of the maleic acid residue, may lower the pK of the latter and increase the degree of dissociation of the monolayer at a constant pH. Finally, it is found that the surface potential and the degree of dissociation of HPA monolayers reproduce the surface potential of the outer face of the nerve membranes and the variation of the sodium conductance with pH and pCa.

The work of detachment, W, of two attached polymers has been determined experimentally for systems consisting of unoxidized and chemically oxidized low density polyethylene (PE) film. The surface density of polar, mainly carbonyl, sites at the surfaces of oxidized polyethylene has been measured by adsorption of calcium ions. Independent measurements of the wettability of these surfaces by pure liquids allows the establishment of a relation between the thermodynamic free energy of adhesion, WA, the polar contribution, γps, of the polymer to this energy and the surface density of polar sites. An attempt to correlate these parameters with the adhesion energy, W, has been made. The importance of the surface polarity on the possible mechanism of polymer self-adhesion is discussed.

Vinblastine sulphate, an antimitotic and anti-inflammatory agent, modifies the thermal behaviour of the model membranes: the dipalmitoylphosphatidylcholine DPPC bilayers. The mixed DPPC and vinblastine sulphate multibilayers in the range of DPPC mole fraction 0.4 to 1 display clearly the gel-liquid crystal (chain melting) transition on the thermograms obtained with a differential scanning microcalorimeter. The molar enthalpy of this transition is slightly depressed by vinblastine sulphate (less than 10%). The temperature-composition phase diagram corresponds to a total insolubility of vinblastine sulphate inside the frozen (gel) bilayers and to a solubility of 0.2 (mole fraction) of vinblastine sulphate inside the fluid (liquid crystalline) bilayers. The dissolved vinblastine sulphate depresses the cooperativity number of the frozen in equilibrium fluid transition of the bilayers very strongly (4- to 5-times). Up to its solubility concentration, vinblastine sulphate increases the amount of the structural water of the bilayers and modifies the thermal behaviour of this water. The 'expelled' vinblastine sulphate molecules are retained by the polar groups of DPPC molecules and screen their electrostatic interactions with the structural water molecules. Below 0 degree C, the amount of the structural water, which forms the aqueous separation between two bilayers, is enhanced by vinblastine sulphate. However, the drug reduces (screens) the bilayers interaction with the structural water molecules.

The melting of the structural water in multibilayer systems is investigated by means of true differential scanning cabrimetry in the range 60°C to + 80°c. Freezing experiments have been carried out too. The multibilayer systems consist in aqueous dispersions of phospholipids at various phospholipid/water amounts or in (phospholipid + additive) dispersed in a given amount of water (140% 60% w/w) for various phospholipid/additive amounts. The phospholipids are DPPC (1-2-dipalmitoyl-sn-glycero-3-phosphocholine), P1 (phosphatidylinositolmonophosphate from wheat) and egg lecithin E-L. The additives are cholesterol Ch, vinblastine VLB and a hydrophobic charged macromolecule (polysoap PS). From the melting thermograms the apparent heat of melting L of the structural water inside the aqueous separation is deduced. It is evident that the additive affects specifically both the structural water and the bilayer thermodynamic behaviour. This result is compared mainly with results of studies of phospholipids swelling in water under various conditions and also to condensation in mixed monolayers.

The chemical constitution of KMnO4/H2SO4-oxidized (sulfated) polyethylene (PE) surfaces has been explored by means of ESCA utilizing chemical shifts, peak intensity data, and chemical tagging reactions. In addition, the adsorption of Ca2+ ions on sulfated PE was quantified by radiotracer measurements. Comparisons have been made with KClO3/H2SO4 and K2Cr2O7/H2SO4 as oxidizing agents and through replacing polyethylene by polystyrene. According to the present study the main chemical groups on a Download : Download full-size image . In the oxidation grooves, dissociable −COOH groups are also present in appreciable amounts. By annealing, a smoother and more homogeneous sulfated surface is produced, the composition of which strongly depends upon the state of the ionic groups at the heat treatment.

Many studies have been undertaken with the aim of proving the potentiality of liposomes and vesicles as drug carriers. However, the results obtained have not yet been developed industrially. One of the reasons for this is the lack of a satisfactory liposome and vesicle preservation method. This study deals with the behaviour of liposomes during lyophilization processes, either in the presence or in the absence of sodium ioxitalamate and maltose. The bilayers are constiluted either by dipalmitoylphosphatidylcholine (DPPC) alone or as a mixture with cholesterol (7/2). The liposome are characterized by their size, their microscopic structure and by release of the active agent. To complete the pharmaceutical study, differential scanning calorimetry (DSC) has been used to analyse the evolution of liposome hydration.

The nonpolar polyethylene is transformed by oxidation into a superficially polar polyethylene with a known surface density of carbonyl groups. The dispersion and polar contributions to the free energy of adhesion for the systems oxidized and unoxidized polyethylene with n -octane, water, and methylene iodide are calculated. The variation of γ s d , γ s p , and γ sl with temperature is found to verify the geometric mean equation for the interfacial free energy γ sl = γ s + γ l − 2 (γ s d γ l d ) 1 2 − 2(γ s p γ l p ) 1 2 . The results are analyzed and the importance of the dispersion and polar interactions and their dependence on temperature is discussed.

The piezothermal behavior of a two-component mixture has been investigated for the first time. Acetone-CS 2 mixture have been examined as a function of pressure and temperature at different compositions. Far from the critical regions each mixture exhibits all the features of a pure liquid. The excess volume of mixing has been determined in this case, as a function of the three variables p, T, and x, with respect to a known reference in the plane (p,x)

Mixed monolayers of the apoprotein A of Folch-Lee proteolipid from the central nervous system myelin and phosphatidyl-inositol monophosphate L from wheat germ have been spread on aqueous NaCl 10 −2 M and pH = 5.5 substrates at room temperature. The ratio [A]/[L] was varied and its effect on the surface pressure and potential of the films as well as on Ca 2+ binding by them were studied (Part II). The model put forward for A in a previous study 11 to interpret the surface potential measurement results was extended to the presently studied system A + L to include the presence of the phospholipid phosphate groups. The theoretical approach worked out previously 11 has been improved. A complementary boundary condition is added, which allows for coupling between the electrical field originating in the permanent dipole moments of the mixed films constituents and the space distribution of the mobile ions.

Vinblastine sulphate (VBLS) encapsulation by small phospholipid (mainly egg lecithin (EL)) vesicles and by large egg lecithin liposomes was studied. It is found that liposomes encapsulate 10 times more drug (∼ 2% mol fraction compared to ∼ 2%o mol fraction) than the small vesicles (60–80 nm diameter). The encapsulation of VBLS may be increased by a factor of 5 when the ab initio (in the dry lipid film) ratio VBLS/EL varies from 0.03 to 1. It is assumed that this increase is due to entrapment of segregated drug in or between the EL bilayers. The release of the entrapped drug into fresh buffer is a slow phenomenon.

Carbonyl groups were formed on the surface of low-density polyethylene by chemical oxidation. The treated surfaces were studied by scanning electron microscopy, ATR, IR spectroscopy, and 45Ca2+ adsorption. Paramagnetic probe ions Mn(II) were adsorbed and the ESR spectra obtained for various surface compositions and thermal treatments of polyethylene. The results obtained show that ESR spectroscopy may become a promising, nondestructive method of analysis of solid polymer interfaces.

True differential calorimetry using a DSC device was used to study the thermal behavior of two hydrated phospholipids: DPPC or dipalmitoyl phosphatidyl choline and PI phosphatidylinositolmonophosphate. The amount of water varied between 15% (w/w) and 60% (w/w). The relevance of ice-melting thermograms to the surface forces emerging from the lipid bilayers and affecting the structural water molecules which constitute the aqueous separation (between bilayers) is demonstrated. The melting of the frozen structural water is not cooperative. For fully hydrated multibilayers, the corresponding molar enthalpy of fusion L is less than 50% of the molar enthalpy for bulk ice melting. In the present report, the difference in the aspects of the thermograms obtained with either the fluid PI or the rigid DPPC bilayers is assigned to a significant thermal expansion of the fluid PI bilayers.

DSC thermograms have been established for two fully hydrated (40 and 50% water w/w) mixtures of a hydrophobic polyelectrolyte and respectively either one acidic or one amphoteric phospholipid. The temperature range of the heating scans, −65 to 50°C, allowed the study of ice melting and of phospholipids gel to liquid-crystal transitions. The phospholipids are wheat phosphatidylinositolmonophosphate PI and synthetic DPPC dipalmitoylphosphatidylcholine. The macromolecular constituent is the polysoap poly(2-methyl-5-vinylhexyl-pyridinium bromide) or PVPC6. Increasing amounts of PVPC6 affect only slightly the transition temperature for both phospholipids although PI is acidic while DPPC is amphoteric. This temperature is 22 to 23°C below 0°C for PI. The effects of PVPC6 on the enthalpy of transition ΔHt for PI and for DPPC are different. For PI, ΔHt decreases sharply in the range of phospholipid mole fraction 0.5-0.6 (cooperativity of PI binding, L. Ter-Minassian-Saraga,J. Colloid Interface Sci.70, 245 (1979 reference 16). For DPPC, it is minimum at x = 0.5. The analysis of ice melting thermograms is original. It provides three classes of water molecules which vary with the ratio PVPC6/phospholipid: bulk water melting at 0°C, supercooled water melting below 0°C, and nonmelting (non-freezing) water of hydration. The last class of water molecules is considerably reduced (dehydration) by the electrostatic interaction between acidic PI and basic PVPC6. It is considerably enhanced by the interpenetration between the amphoteric DPPC and PVPC6 molecules. Pure PI and DPPC do not display significant specificity toward water binding. An interpretation is proposed for the shape of the ice-melting peaks obtained for lamellar systems. It is based on the hypothesis that the free energy of water inside the aqueous separation between the bilayers is lower than in bulk water on account of molecular interactions water-bilayer. The interpretation is satisfactory for the amphoteric DPPC pure or mixed with PVPC6. The relevance of the present results to “condensation” in mixed monolayers and to biological systems is discussed.

The behaviour of three egg-lecithin (EL)—water (W) mixtures, 60% (w/w):I, 50% (w/w):II and 30% (w/w):III, squeezed out or sucked in between two mica surfaces was investigated using an apparatus designed by J.N. Israelachvili. Mixture I is a lyotropic-smectic liquid crystal (LSLC), in contrast to II and III in which the LSLC is in equilibrium with a separated phase of excess water. The force F applied to the micasheet holders, the “separation” D between the mica surfaces and the average refractive index were measured for 1 A stepwise-thinning process was mainly observed on compressing mixtures I and II from separation 30 The contact area of the flattened-mica sheets increased with the force F at separation Dmin. Assuming that an effective elastic parameter can be defined for our composite system (mica sheet + glue), we interpret the F—contact-area dependence using the theory of Johnson et al. and deduce values of average normal pressures or stresses of the order of 10 mN m−2 on the flat mica—mica contact. At such pressures the values of λ and the repeat distance of the LSLC formed by EL + W and measured by X-ray diffraction are similar. The refractive index n of I is independent of separation for Dmin

The thermal effect following a pressure variation has been measured up to 400 MPa for various organic compounds under isothermal conditions. An entropy variation proportional to the expansivity can be deduced for homogeneous phases. For coexisting phases the measurement gives the entropy of the transformation. Piezothermograms are established for n -hexane, n -hexadecane, butane-1,4-diol, hexamethylbenzene, and liquid crystals. Melting, solid-state transformation, and fluid-state transformation are examined.

The piezothermal method was used to determine the thermal expansivity of benzene up to 4 kbar along 9 isothermal paths, in the range 250–350 K. It is shown that, in the solid phases, the thermal expansion is a function of volume only. This property which appears to be typical of the solid phase still holds in the premelting region. This suggests that premelting is concerned only with the evolution of the solid phase.

The expansivity of liquid CO2 and of n‐butane is determined as a function of pressure up to 4 kbar, from the melting temperatures up to the critical temperatures. The experimental method is piezothermal. The set of data is processed through a fit with a multipoint Pade approximant using an algorithm due to Werner. This particular technique determines, in its reduced form, the unique rational function relevant to the problem. The expansivity of the whole liquid phase is described in terms of a simple equation with four coefficients which enables calculation of the other thermodynamic properties. The general aspect of the phenomenological equations is discussed in this instance, underlining the particular behavior of the heat capacity as a function of pressure.

Cycles of compression-expansion of mixed monolayers formed by spreading mixtures of an acidic phospholipid, Na phosphatidylinositolmonophosphate, extracted from wheat, and the polysoap poly(2-methyl-5-vinyl-hexylpyridinium bromide) have been performed. The phospholipid is a ligand for the polysoap monomers. The films collapse and respread reversibly when the films contain an excess of the phospholipid. When the films contain an excess of the polysoap or only the pure polysoap, polysoap molecules desorb or are ejected into the aqueous substrate when the film surface pressure exceeds a first collapse pressure. A second collapse pressure is attained at higher surface pressures when the excess polysoap has desorbed. Therefore, in contrast to the mixed films with an excess of phospholipid, the collapsed and irreversibly desorbed pure polysoap cannot respread. The relevance of these experiments to the behavior of biological membranes and of the monolayers at the surface of the liquid lining of lung alveoli is considered.

Mixed monolayers of the apoprotein A of Folch-Lees proteolipid from the central nervous system myelin and phosphatidyl-inositol monophosphate L from wheat germ have been spread at the surface of aqueous NaCl 10−2 M and pH = 5.5 substrates at room temperature. The ratio A/L was varied and its effect on the surface pressure and potential of the films as well as on Ca2+ binding by them were studied. The theoretical approach worked out in the preceding Part I is used to interpret the results. Numerical treatment of the Poisson-Boltzmann equation set up in Part I using the experimental results provides a small penetration thickness for the mobile ions: l0 = 1-3 A. To discuss electrostatic interactions between lipid and protein, an appropriate definition of the composition of the mixed monolayers is suggested: the fraction xE of net charges of A relative to the total charge due to the sum of the net charges of the constituents. It is found that for the critical value xE ~ 0.3 of its composition the mixed film A + L at the collapse point displays discontinuities in the following properties: the collapse surface pressure and potential, and the permanent dipole moment of lipid. The relative dielectric constant is independent of composition and equal to 2 for xE < 0.5 (the lipid rich films) and gradually moves to 15 in the interval range 0.5 < xE < 1. It follows that in the mixed monolayers we study at collapse point, the occuring conformational changes observed originate mainly in the lipid constituent.

Monolayers of hexadecyltrimethylammonium bromide produce homeotropic or planar alignments of liquid crystals p-n-methoxybenzilidene aniline and pmethoxyphenylazo-p-butylbenzene.

Etude de la distribution d'equilibre d'un compose soluble entre un support liquide et sa phase superficielle dans le cas d'essais de penetration. Ce systeme a 3 composants (la phase aerienne negligee) est forme par 2 constituants de phase globale et superficielle, 0 et 2, et par une substance soluble en surface, 1, la couche monomoleculaire etalee. La phase superficielle est semi-ouverte: fermee a 1 et ouverte a 0 et 2

Flux calorimetry is employed to obtain ( ∂V ∂T ) p and ( ∂V ∂p ) T by use of Maxwell's thermodynamic relations. The method thus provides a measurement of thermal expansivity and isothermal compressibility, and also of heat capacity, using a single liquid sample. Results for hexadecane, butane-1,4-diol, 1,2,4-trimethylbenzene, and cyclohexanol are compared with previous values.

Mixed films of phosphatidylinositol monophosphate and of the apoprotein of the Folch—Lees proteolipid from myelin were continuously compressed and the rates of their surface pressure increase with time were measured at various positions in the film. These rates decreased when the distance from the barrier increased. This behavior may be interpreted by using the theory developed in Part I [Dimitrov et al., J. Colloid Interface Sci. 65, 483 (1978)] and a Maxwell model for a viscoelastic two-dimensional fluid. The specific relaxation time θ thus deduced is very large for the lipid-rich mixed films for our experimental conditions. It is smaller when an excess of protein charges is present.

For two types of mixed monolayers the surface pressure and surface potential have been measured as a function of their composition. They were formed by spreading of an acidic phospholipid and either a basic polysoap or a basic hydrophobic protein from myelin. The reaction was followed by using a radioactive counterion as an indicator. It was found that with the polysoap, highly charged by dissociation, the reaction with the acidic lipid was cooperative, contrary to the case of the protein which was not highly charged. For both, however, screening of the electrostatic repulsion between the ionized groups of the polyions by the lipid charge appears as a “condensation” of the polyions and of the lipid. Models are suggested to interpret this condensation and the mutual structuration of the polyions and of the lipid molecules. They are extended to biological membrane structures in the absence or in the presence of applied force or electrical fields.

The heat liberated by isothermal compression permits the determination of the thermodynamic properties of liquid water−heat capacity, compressibility, and expansivity. The results, as a function of pressure and temperature, have been extrapolated as far down as −40 °C. They confirm the existing data in the region of the supercooled liquid and also the existence of a divergence of the measured properties. This could be explained as a lambda transition occuring at −45 °C on isobars p = 0. The abnormal heat capacity which characterizes this transition is well described as a function of the temperature by a formula with critical coefficients as already suggested by others.

The effect of two anti-cancer agents, vinblastine sulphate (VLBS) and vincristine sulphate (VCRS), on the gel-liquid crystal transition of fully hydrated dipalmitoylphosphatidylcholine (DPPC) has been studied by differential scanning calorimetry (DSC). DSC diagrams were established for various mixtures of DPPC + agent and a fixed (50%) amount of water. It is concluded that VLBS perturbs the hydrated DPPC structure more strongly than VCRS. This conclusion confirms the idea proposed by Hort-Legrand and Metral [5] that these anti-mitotic drugs may also affect the functioning of cell membranes.

Previous results (Castagna et al. (1979) FEBS Lett. 100, 62-66; Fisher et al. (1979) Biochem. Biophys. Res. Commun. 86, 1063-1068) indicated us that the active tumor promoter TPA (12-O-tetradecanoylphorbol 13-acetate) decreased fluorescence polarisation of diphenylhexatriene in lymphoblastoid and rat embryo cells. In the present study, experiments aimed at examining the molecular interactions of tumor promoters with cell membrane components are performed with fully hydrated multibilayers of 1,2-diacyl-sn-glycero-3-phosphocholine (DPPC) into which increasing amounts of TPA are inserted. The thermotropic behaviour of both the phospholipid bilayers and the interbilayer water was investigated using the differential scanning calorimetry (DSC) and the approach of Ter-Minassian-Saraga et al. ((1982) J. Colloïd Interface Sci. 81, 369-383). The major effects of the tumor promoter are confined to concentrations up to 20% mol fractions of TPA. In this range of concentrations the incorporation of TPA into liposomes decreases the phase-transition temperature but did not affect delta HDPPC. Furthermore TPA increases the hydration of the multibilayers. Above 20% mol fractions of TPA, a different thermal behaviour of the system which might suggest morphological rearrangements was observed. The lipid state in TPA-treated liposomes was monitored by fluorescence polarisation using diphenylhexatriene as a lipophilic fluorescent probe and the phase-transition temperature was calculated. The phase transition temperatures determined by both methods were in good agreement. The lowering of this temperature and the decay of fluorescence anisotropy of diphenylhexatriene were parallel. Those effects are consistent with the "fluidising' effect of TPA on DPPC.

The amounts of structural and hydration water of the fully hydrated (DPPC) dipalmitoylphosphatidylcholine sub-gel phase have been studied using the approach of Ter-Minassian-Saraga, L., and Madelmont, G. (J. Colloid Interface Sci. 85, 375–388 (1982)). These amounts are not significantly different from those of the Lβ′ phase. Also, the molar enthalpy L of melting of the frozen structural water is the same for both gel phases. The interesting result which emerges from our experiments is the enhancement of the resolution of the peak (in the heating thermogram) corresponding to the frozen structural water melting. The explanation provided for this enhancement is that long annealing durations of the gel phase, inside which the water is liquid, favors the phase separation between the excess bulk water and the sub-gel phase and the crystallization of DPPC chains inside the larger liposomes thus formed.

The effect of the antimitotic drug vinblastine sulfate has been studied on fully hydrated dipalmitoylphosphatidylcholine (DPPC) liposomes in the temperature range 0 degrees to 60 degrees using differential scanning calorimetry and electron spin resonance spectroscopy with two fatty acid spin labels. In the gel phase, vinblastine interacts essentially with the DPPC polar heads and induces an important disorganization of the phospholipidic bilayer. The co-operativity of the main thermal transition is decreased. In the crystal-liquid phase, the drug penetrates inside the artificial membrane and induces the formation of domains which increased thermal stability. These effects are opposite to those observed with the drug isaxonine which is used to reduce the axonal degenerating effects due to vinblastine.

Polymerization with gamma and x rays was studied in the range --75 deg to -- 196 deg , using mostly the taermoanalytical method. The doses of radiations used, although usually less than 2000 r, cause high degrees of conversion. At the lowest temperatures the polymerization behaves explosively, either on warming up or during the irradiation itself, depending on the dose. This type of polymerization was interpreted in terms of an internal warming up due to the accumulation of growing chains. An increase of a few degrees in internal temperature with respect to the temperature external to the reaction medium is sufficient to provoke an explosion. An activation energy of about 3 kcal/ mole was determined. At higher temperatures the polymerization proceeds in a thermally stationary state, because the chain initiation and termination occur during the irradiation. (auth)

Maleic anhydride was grafted on the surfaces of the low density polyethylene films by free radical polymerization. The reaction was allowed to run for a short period of time, such that only a very low degree of grafting was obtained. After hydrolysis, the grafted samples were equilibrated with solutions of different alkali and organic cations at constant pH. Their wettability towards the equilibrating solutions was determined by contact-angle measurements. It varies with the nature of the neutralizing cation and the pH of the wetting solution. The works of adhesion and the field strengths of Ca Na substituted surfaces were determined as a function of the ionic percentage of calcium.

The adsorption of a monolayer of hexadecyltrimethylammonium bromide (CTAB) on glass-slides allows the preparation of a monocrystal of p-n -methoxybenzilidene- p -butylaniline (MBBA) oriented either prependicularly to surfaces (homeotropic anchorage) or in a direction parallel to surfaces (planar anchorage). These orientations are dictated by the surface density and the structure of the adsorbed CTAB monolayers and confirm a model of orientation of a liquid crystal by physico-chemical coupling.

The wettability of oxidized polyethylene films was studied with pure liquids (water and methylene iodide) and practically nonpolar mixtures of Decalin and methylene iodide. A linear variation was found of the wettability of these films with the chemical composition of their surfaces (determined by adsorption of radioactive 45 Ca ions). A value of γ s d for the polyethylene was found with the nonpolar mixtures of methylene iodide and Decalin and the values of the solid-liquid polar interactions ( I sl P ) for oxidized polyethylene were deduced. Dipole-dipole and induced dipole-dipole interactions between the pure liquids and the oxidized and unoxidized polyethylene were calculated for two possible orientations of the hydrocarbon chains to the surface and compared with the experimental results. Generally a poor agreement was obtained, mainly due to the difficulty in estimating the correct values for the distances between molecules or groups. However, a better agreement was obtained assuming that the chains were perpendicular to the surface.

The entropy Variation ds(T,p) may be determined with accuracy when computed from heat capacity and expansivity measurements from $$ds = {c_P}\left( {\frac{{dT}}{T}} \right) - \alpha v\,dp$$ (1) When the variable is only the temperature, the measurement of cp provides a convenient and sensitive but partial method for the study of the phase transitions. Extension to include the variable pressure requires elaborate techniques and as a consequence the entropy data as a function of pressure are scarce and unreliable. The gap may be filled when the second term in (1), (∂s/∂p)T, is measured directly. This term has the meaning of an entropy Variation resulting from isothermal liberation of the heat of compression and has been shown to be measurable by calorimetric methods at high pressures [1–3]. Following these methods, successive isotherms are determined as a function of pressure and the result is a full description of the phases and of their mutual transformations. The present paper deals with such piezothermal results obtained with benzene and carbon tetrachloride under their liquid and solid states up to pressures of 4 and 7 kbars.

Mesures de dilatation et de compressibilite de 200 a 450 K jusqu'a 4 kbar. On observe une anomalie dans les capacites calorifiques a basse temperature et haute densite