Prospective Phase II Study of Radiotherapy Dose Escalation in Grade 4 Glioma Using 68Ga-Pentixafor PET Scan.

AIMS: Local failure remains the major concern in grade 4 glioma or glioblastoma (GBM). Pilot studies have shown a radiotherapy (RT) dose-response relationship in GBM. Here we present our preliminary data of RT dose escalation using 68Ga-Pentixafor PET scan. High 68Ga-pentixafor uptake in glioma cells helps in sharp demarcation between tumour and normal brain. MATERIALS AND METHODS: This phase II prospective study was conducted from 2018 to 2020. Thirty, biopsy-proven cases of grade 4 glioma were included. All patients underwent post-operative MRI of the brain and 68Ga-Pentixafor PET scan. RT was planned in 2-phases. Phase-1 GTV (GTV1) comprised of T2/flair abnormality, PET-avid disease and post-op cavity. A margin of 2cm was given to GTV-1 to create phase-1 CTV (CTV1), which was further expanded to 0.5cm to generate phase-1 PTV (PTV1). A radiation dose of 46Gy/23fr was prescribed to PTV-1. Phase-2 GTV (GTV2) consisted of CT/MRI contrast-enhancing lesion, PET avid disease and post-op cavity. A margin of 0.5 cm was given to GTV2 to create phase-2 CTV (CTV2) which was expanded to 0.5 cm to create phase-2 PTV (PTV2). RT dose of 14 Gy/7 fr was prescribed to PTV2. PET avid disease was delineated as GTV PET and a margin of 3mm was given to generate PTV-PET which received escalated RT dose of 21 Gy/7fr by simultaneous integrated boost (SIB) in phase 2 (Total dose to PTV PET = 67 Gy/30 fr). All patients received concurrent and adjuvant temozolomide. The data was prospectively maintained in Microsoft Excel sheet. SPSS v 23 was used for statistical analysis. The primary endpoints were estimation of the overall survival (OS) and progression-free survival (PFS), and secondary endpoint was to measure the incidence of radiation necrosis. Categorical variables were reported as frequency and percentage and quantitative variables were reported as median and range. RESULTS: Data from thirty patients were analysed. A median OS of 23 months was observed with estimated 1, 2 and 3 years OS of 90%, 40% and 17.8% respectively. A significant association of OS was seen with the extent of surgery (p = 0.04) and kernofsky performance status (p = 0.007). No patient developed significant radiation necrosis. CONCLUSIONS: The index study did not show any survival benefit from dose escalation RT. However, all of the patients tolerated the treatment well and none of them developed radiation necrosis. Considering the small sample size as a limitation of the index study, the role of 68Ga-pentixafor PET scan for radiation dose escalation should be further explored. CLINICAL TRIAL NUMBER: CTRI/2019/05/019146.

Cryogenic conditioning of microencapsulated phase change material for thermal energy storage.

Microencapsulation is a viable technique to protect and retain the properties of phase change materials (PCMs) that are used in thermal energy storage (TES) applications. In this study, an organic ester as a phase change material was microencapsulated using melamine-formaldehyde as the shell material. This microencapsulated PCM (MPCM) was examined with cyclic cryogenic treatment and combined cyclic cryogenic heat treatment processes. The surface morphology studies showed that the shell surfaces had no distortions or roughness after cryogenic treatment. The cryogenically conditioned microcapsules exhibited diffraction peak intensity shifts and crystal structure changes. The onset of melting for the nonconditioned and conditioned microcapsules were measured to be 8.56-9.56 °C, respectively. Furthermore, after undergoing the cryogenic and heat treatment processes, the PCM microcapsules had appreciable latent heat capacities of 39.8 kJ/kg and 60.7 kJ/kg, respectively. Additionally, the microcapsules were found to have good chemical stability after the cryogenic treatment. In addition, the cryogenically conditioned microcapsules were found to be thermally stable up to 128.9 °C, whereas the nonconditioned microcapsules were stable up to 101.9 °C. Based on the test results, it is obvious that the cryogenically conditioned microcapsules exhibited good thermal properties and are very desirable for cool thermal energy storage applications.

Preparation and electrochemical characterization of cation- and anion-exchange/polyaniline composite membranes.

Composite membranes were prepared by chemical polymerization of a thin layer of polyaniline (PANI) in the presence of a high oxidant concentration on a single face of a sulfonated cation-exchange membrane (CEM) and quaternary aminated anion-exchange membrane (AEM). IR and SEM studies for both types of membranes confirmed PANI loading on the ion-exchange membranes. PANI composite ion-exchange membranes were characterized as a function of the polymerization time by ion-exchange capacity, coating density, and membrane conductance measurements. Membrane potential measurements were performed in various electrolyte solutions in order to observe the selectivity of these membranes for different types of counterions. Membrane potential data in conjunction with membrane conductance data was interpreted on the basis of frictional considerations between membrane matrix and solute. Electrodialysis experiments, using PANI composite ion-exchange membranes with 4 h polymerization time, were performed in single and mixed electrolyte solutions for observing electromigration of solute across PANI composite ion-exchange membranes. Relative dialytic rates of Na(2)SO(4), CaCl(2), and CuCl(2) were estimated with reference to NaCl on the basis of electrodialysis experiments and it was concluded that it is possible to separate different electrolytes using PANI composite ion-exchange membranes.

Studies on the electrochemical and permeation characteristics of asymmetric charged porous membranes.

Asymmetric charged porous membranes were prepared by imbedding 10% (W/W) ion-exchange resin in cellulose acetate binder. Membrane potential and conductance measurements have been carried out in sodium chloride solutions at different concentrations to investigate the relationship between concentration of fixed charges and electrochemical properties of developed nonselective cation- and anion-exchange membranes. Counterion transport number and permselectivity of these membranes were found to vary due to the presence of ion-exchange resin. The hydrodynamic and electroosmotic permeability of sodium chloride solutions has been studied in order to compute equivalent pore radius. For cation- and anion-exchange membranes good agreement was observed between pore radius values estimated from hydrodynamic and electroosmotic permeability coefficient separately, while for nonselective membranes no correlation was found. Membrane conductance data, along with values of concentration of fixed charges, were used for the estimation of the tortuosity factor, salt permeability coefficient, and frictional coefficient between solute and membrane matrix employing an interpretation by nonequilibrium thermodynamic principles based on frictional forces. Moreover, surface morphological studies of these membranes also have been carried out and the membranes were found to be reasonably homogeneous.

Studies on exchange equilibria of cations between cation-exchange membranes and electrolytic solutions.

The variations of the selectivity coefficient K(A)(B) between Na(+)-H(+), Na(+)-K(+), and Na(+)-Cu(2+) systems and the separation factor alpha(A)(B) between Na(+)-Cu(2+) and K(+)-Cu(2+) systems in cation-exchange membranes as functions of loading and particle size of resin have been measured. The exchange affinities of all the membranes increase as H(+)

A new membrane probing steroidal spin label: synthesis and applications.

The applicability of a new steroidal spin label, 3-oxo-androstan-17 beta-yl-(2",2",6",6"-tetramethyl-N-oxyl) piperidyl butan-1',4'-dioate, in studying the phase transition properties of model membrane L-alpha-dipalmitoyl phosphatidyl choline (DPPC) in the presence and absence of drugs has been explored. Its synthesis and characterization has been described herein. Besides, the localization of this spin label in lipid liposomes has been studied using electron spin resonance (ESR), differential scanning calorimetry (DSC) and 1H and 31P NMR spectroscopic techniques. The label has also been used to study the permeability of epinephrine into membrane. The results show that the spin label has a good potential as a spin probe in the study of biomembranes.

The allele frequency of mutations in four genes that confer enhanced susceptibility to venous thromboembolism in an unselected group of New York State newborns.

The frequencies of Factor V G1691A (FVL), prothrombin (PT) G20210A, 5'10'methylenetetrahydrofolate reductase (MTHFR) C677T, and methionine synthase (MS) A2756G (four mutations associated with an increased risk of venous thromboembolism [VTE]) were determined in a sample of approximately 1500 New York State residents. Dried blood spots from approximately equal numbers of Caucasians, African-Americans and Hispanics were anonymously obtained from the New York State Department of Health Newborn Screening Program. Following PCR amplification of dried blood spot DNA, allele-specific oligonucleotide hybridization was used to detect mutant alleles. The total number of individuals at increased genetic risk for VTE was 271 (17.5%) of the 1553 persons tested. Increased genetic risk was defined as the heterozygous state for FVL or PT and the homozygous state for the MTHFR or MS polymorphisms. Sixteen individuals had more than one genetic risk factor. The MS gene variant allele frequencies for African-Americans and Hispanics are the first to be reported. This report also provides an estimate of the variant PT allele in the largest group of Hispanics studied to date.

A novel steroidal spin label for membrane structure studies: synthesis and applications.

2,2,6,6-Tetramethyl piperidine-N-oxyl nitroxyls are known to partition between aqueous and lipid phases, thus serving as probes to study membrane dynamics. The synthesis of a novel steroidal spin label, 3alpha-hydroxycholan-24-yl-(2",2",6",6"-tetramethyl-N-oxyl)p iperidyl butan-1',4'-dioate, containing 2,2,6,6-tetramethylpiperidine-N-oxyl moiety covalently bonded to the side chain in 3,24-caprostan-diol has been described. The localization of this spin label in model biomembranes has been studied by using electron spin resonance, differential scanning calorimetry, and 1H and 31P NMR spectroscopic techniques. Its applicability in studying the phase transition properties of model membrane L-alpha-dipalmitoyl phosphatidyl choline in the presence and absence of drugs has been described by using electron spin resonance. The label has also been used to study the permeability of epinephrine into membrane. The results have shown the applicability of the spin label as a potential spin probe in the study of biomembranes.

1-[2-Hydroxy-3-octadecan-1'-oate]propyl-2'',2'',5'',5''-tetramethyl pyrolidine-N-oxyl-3''-carboxylate as a potential spin probe for membrane structure studies.

The synthesis of a new minimum steric perturbing proxyl nitroxide, which is a derivative of glycerol and contains a stearic acid moiety, has been carried out. Its localization in model membrane L-alpha-dipalmitoyl phosphatidyl choline (DPPC) was ascertained with the help of ESR, DSC, 1H and 31P NMR techniques. The nitroxide was used for detecting the changes in the phase transition temperature of the model membranes in the presence and absence of drugs. The permeation of the vasodilating drug epinephrine has also been studied using this spin label. The results prove the potential applicability of the new spin probe in the spin labeling of biomembranes.

Differential behavior of (25R)-5,6-epoxyspirostan-22 alpha-O-3 beta-ol and (25R)-5,6-epoxyspirostan-22 alpha-O-3 beta, 4 beta-diol toward Dowex.

The acid-catalyzed hydrolytic cleavage of the 5,6-epoxyspirostane derivatives by the cation exchange resin Dowex 50W X8 has been exploited with the goal of developing synthetic protocols toward 3,4,5,6-polyhydroxyspirostane analogs that can serve as intermediates to potential biologically active compounds. Whereas the diastereomers (25R)-5 alpha, 6 alpha-epoxyspirostan-22 alpha-O-3 beta-ol and (25R)-5 beta, 6 beta-epoxyspirostan-22 alpha-O-3 beta-ol yield two products, (25R)-6 beta-methoxyspirostan-22 alpha-O-3 beta, 5 alpha-diol and (25R)-spirostan-22 alpha-O-3 beta, 5 alpha, 6 beta-triol on Dowex treatment in water-methanol, the alpha- and beta-diastereomers of the 5,6-epoxy derivative of 3 beta, 4 beta-diol provide a single product, (25R)-3 beta, 6 beta-dihydroxy-5 alpha-spirostan-4-one, in good yields. The structures of these products have been confirmed using 1H NMR, 13C NMR, and 1H-1H J-correlated spectroscopies. Multifunctional product formation suggests tremendous utility of Dowex in steroid synthesis. The product formation has been rationalized on the basis of differential conformational constraints of the A/B rings of the different epoxides in directing the reaction course. The reaction shows an interesting example of stereoelectronic effect of a single hydroxy group in discriminating solvent participation.

2'-(3 alpha-Benzyloxy-24-norcholan-23-yl)-2',4',4'-trimethyl-4',5'- dihydrooxazoline-N-oxyl as a potential spin probe for model membranes.

A new steroidal doxyl (4,4-dimethyloxazolidine-N-oxyl) nitroxide (SDN) viz. 2'-(3 alpha-benzyloxy-24-norcholan-2'-yl)-2',4',4'-trimethyl-4',5'- dihydrooxazoline-N-oxyl has been synthesized. This is expected to have higher mobility over other spin labels reported earlier. The localization of this spin probe in lipid bilayers has been determined using 1H NMR and 31P NMR techniques. The alterations induced by drugs in the membrane characteristics such as phase transition and permeability have been investigated using electron paramagnetic resonance (EPR) techniques. The results show the applicability of SDN as a potential spin probe in the study of biomembranes.

Proxyl nitroxide of lithocholic acid: a potential spin probe for model membranes.

A new steroidal proxyl (2,2,5,5-tetramethylpyrrolidine-N-oxyl) nitroxide (SPN), with the proxyl nitroxide moiety in the pendant side chain of the steroid, has been synthesized. Its localization in lipid bilayers was ascertained with the help of 1H NMR and 31P NMR experiments. The effects of the nitroxide group in SPN incorporated into the bilayer on 13C relaxation times are interpreted qualitatively in terms of localization of the nitroxide group within the bilayer structure. The nitroxide SPN was used to monitor changes in membrane fluidity and permeability induced by local anaesthetics, mepivacaine and xylocaine and the antikeratinizing agent, azelaic acid. The results conclusively proved the applicability of the new steroidal proxyl nitroxide (SPN) as a potential spin probe for spin labeling studies.

Conformational analysis of A and B rings in 2-, 4-, and 6-bromosubstituted steroidal 4-en-3-ones by nuclear magnetic resonance.

The conformational preference of A and B rings in four differently functionalized bromosubstituted 4-en-3-one steroids is studied by concerted application of high-resolution one- and two-dimensional nuclear magnetic resonance (NMR) techniques, such as homonuclear and heteronuclear correlated spectroscopy, transient and steady-state nOe spectroscopy, temperature-dependent chemical chemical shift variation, and application of a modified Karplus equation. The steroids studied include 6 beta-bromocholest-4-en-3-one (3), 4,6 beta-dibromocholest-1,4-dien-3-one (2), 2 alpha,4,6 beta-tribromocholest-4-en-3-one (1), and (25R)-2 alpha,6 beta-dibromospirost-4-en-3-one (4). Steroids 1-4 were prepared by either acid-catalyzed or free-radical bromination from appropriate 4-en-3-one steroid. The study has yielded an insight into the factors responsible for conformational preferences of the A and B rings of these bromosubstituted steroids. Bromosubstitution at the 2 alpha position is responsible for the inversion of the A ring to inverted 1 beta,2 alpha-halfchair conformation. The electronic interaction between 4-bromine and carbonyl oxygen distorts the A-ring conformation further. Inversion of the A ring has a concomitant effect of distortion in the chair form of the B ring. Conformational preferences of A and B rings are not found to be influenced by transmission effect of a side chain or oxygenated ring system. Temperature-dependent NMR studies indicate the reduced conformational flexibility of the A ring for 2 alpha-bromosubstituted steroids. Complete assignment of the 13C and 1H resonances of two of the steroids studied (3 and 4) is presented.

New steroid haptens for radioimmunoassay: synthesis of steroids substituted with thioether or ester linkages at the 2 alpha-position.

Haptens with bridge at the 2-position have not yet been explored. Radioimmunoassays with antibodies directed against 2 alpha-alkyl bridged steroid haptens are expected to be highly specific due to greater topographical exposure and similarity in conformation to the native steroid. The 2 alpha-alkyl bridged haptens were synthesized by first adding a cyclopropane ring to 2-methylene-4-en-3-one. Selective opening of the three-membered ring with trimethyl silyl iodide and transformation of the iodo group gave a carbocyclic acid, the desired analog for conjugation with protein.