Shear-induced phase transition in the aqueous solution of an imidazolium-based ionic liquid.

An ionic liquid (IL) is a salt in the liquid state that consists of a cation and an anion, one of which possesses an organic component. Because of their non-volatile property, these solvents have a high recovery rate, and, hence, they are considered as environment-friendly green solvents. It is necessary to study the detailed physicochemical properties of these liquids for designing and processing techniques and find suitable operating conditions for IL-based systems. In the present work, the flow behavior of aqueous solutions of an imidazolium-based IL, 1-methyl-3-octylimidazolium chloride, is investigated, where the dynamic viscosity measurements indicate non-Newtonian shear thickening behavior in the solutions. Polarizing optical microscopy shows that the pristine samples are isotropic and transform into anisotropic after shear. These shear thickened liquid crystalline samples change into an isotropic phase upon heating, which is quantified by the differential scanning calorimetry. The small angle x-ray scattering study revealed that the pristine isotropic cubic phase of spherical micelles distort into non-spherical micelles. This has provided the detailed structural evolution of mesoscopic aggregates of the IL in an aqueous solution and the corresponding viscoelastic property of the solution.

How 1,n-Bis(3-alkylimidazolium-1-yl) Alkane Interacts with the Phospholipid Membrane and Impacts the Toxicity of Dicationic Ionic Liquids.

Ionic liquids based on doubly charged cations, often termed dicationic ionic liquids (DILs), offer robust physicochemical properties and low toxicity than conventional monocationic ionic liquids. In this design-based study, we used solid-state NMR spectroscopy to provide the interaction mechanism of two DILs, 1,n-bis(3-alkylimidazolium-1-yl) alkane dibromide ([C2n(C7-nIM)2]2+·2Br-, n = 1, 6), with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG) phospholipid membranes, to explain the low toxicity of DILs toward HeLa, Escherichia coli, Bacillus subtilis, and Saccharomyces cerevisiae cell lines. Dications with a short linker and long terminal chains cause substantial perturbation to the bilayer structure, making them more membrane permeabilizing, as shown by fluorescence-based dye leakage assays. The structural perturbation is even higher than [C12(MIM)]+ monocations, which carry a single 12-carbon long chain and exhibit a much higher membrane affinity, permeability, and cytotoxicity. These structural details are a crucial contribution to the design strategies aimed at harnessing the biological activity of ionic liquids.

Role of Cholesterol in Interaction of Ionic Liquids with Model Lipid Membranes and Associated Permeability.

In this work, we explored how the amount of cholesterol in the lipid membrane composed of phosphatidylcholine (POPC) or phosphatidylglycerol (POPG) affects the interaction with 1-dodecyl-3-methylimidazolium bromide ([C12MIM]+Br-) ionic liquids using various biophysical techniques. On interacting with the membrane, [C12MIM]+Br- leads to enhanced membrane permeability and induces membrane fusion, leading to an increase in vesicle size. The 2H-based solid-state NMR investigations of cholesterol-containing lipid membranes reveal that [C12MIM]+Br- decreases the lipid chain order parameters and counteracts the lipid condensation effect of cholesterol to some extent. Therefore, as the amount of cholesterol in the membrane increases, the membrane effect of [C12MIM]+Br- decreases. The effect of [C12MIM]+Br- on the membrane properties is more pronounced for POPC compared to that of POPG membranes. This suggests a dependence of these effects on the electrostatic interactions, indicating that the influence of [C12MIM]+Br- varies based on the lipid composition. The findings suggest that the presence of cholesterol can modulate the effect of [C12MIM]+Br- on membrane properties, with variations observed between POPC and POPG membranes, highlighting the importance of lipid composition. In short, this study provides insights into the intricate interplay between cholesterol, the lipid membrane, and the ionic liquid [C12MIM]+Br-.

Measuring Ca2+-induced structural changes in lipid monolayers: implications for synaptic vesicle exocytosis.

Synaptic vesicles (SVs) are small, membrane-bound organelles that are found in the synaptic terminal of neurons. Although tremendous progress has been made in understanding the protein machinery that drives fusion of SVs with the presynaptic membrane, little progress has been made in understanding changes in the membrane structure that accompany this process. We used lipid monolayers of defined composition to mimic biological membranes, which were probed by x-ray reflectivity and grazing incidence x-ray diffraction. These techniques allowed us to successfully monitor structural changes in the membranes at molecular level, both in response to injection of SVs in the subphase below the monolayer, as well as to physiological cues involved in neurotransmitter release, such as increases in the concentration of the membrane lipid PIP(2), or addition of physiological levels of Ca(2+). Such structural changes may well modulate vesicle fusion in vivo.

Effect of PIP2 on bilayer structure and phase behavior of DOPC: an X-ray scattering study.

Phosphatidylinositol 4,5-bis-phosphate (PIP(2)) is an important lipid in regulation of several cellular processes, particularly membrane fusion. We use X-ray diffraction from solid-supported multilamellar 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/PIP(2) samples to study changes in bilayer structure and the lyotropic phase behavior induced by physiologically relevant concentrations of PIP(2) . Electron-density profiles reconstructed from X-ray reflectivity measurements indicate that PIP(2) strongly affects structural parameters such as lipid head-group width, bilayer thickness, and lamellar repeat spacing of DOPC bilayer stacks. In addition, at lower degrees of hydration, a few molar per cent of PIP(2) facilitates stalk-phase formation and also leads to formation of a hexagonal phase, which is not observed in pure DOPC. These results indicate that the role of PIP(2) in membrane fusion could be, in part, due to its effect on the properties of the lipid bilayer matrix. Furthermore, coexistence of two lamellar phases with different lattice constants is observed in single-component PIP(2) samples.

Thermodynamics and structure of model bio-membrane of liver lipids in presence of imidazolium-based ionic liquids.

Ionic liquids (ILs) are the attractions of researchers today due to their vast area of potential applications. For biomedical uses, it becomes essential to understand their interactions with cellular membrane. Here, the membrane is mimicked with lipid bilayer and monolayer composed of liver lipids extract. Three archetypal imidazolium based ILs, 1-decyl-3-methylimidazolium tetrafluoroborate ([DMIM][BF4] or [C10MIM][BF4]), 1-octyl-3-methylimidazolium tetrafluoroborate, ([OMIM][BF4] or [C8MIM][BF4]) and 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM][BF4] or [C2MIM][BF4]) having different alkyl chain lengths are used in the present study. The isothermal titration calorimetry (ITC) measurements showed that [DMIM][BF4] interacts strongest with the liver lipid membrane compared to other two ILs which have relatively shorter alkyl chain length. The low values of stoichiometry ratio of ILs indicates that ILs penetrate within the core of the lipid bilayer. The interaction of ILs with the liver lipid membrane is found to be mainly driven by entropy which could be due to the change in the structure of the lipid membrane at local or global scales. Dynamic light scattering (DLS) measurements indicate that there are no changes in the size of vesicles due to addition of [DMIM][BF4] indicating stability of the vesicles. On the other hand, x-ray reflectivity (XRR) measurements showed a concentration dependent change in the monolayer structure. At low concentration of the IL, the monolayer thickness decreases, exhibiting an increase in the electron density of the layer. However, at higher concentrations, the monolayer thickness increases proving a concentration dependent effects of the IL on the arrangement of the molecules.

Imidazolium-based ionic liquids cause mammalian cell death due to modulated structures and dynamics of cellular membrane.

Here, we report the toxic effects of various imidazolium-based ionic liquids (ILs) with varying hydrocarbon chain lengths, on different human cell lines. Multiple biological assays have shown that the ILs with long hydrocarbon chains have stronger adverse effect especially on human liver cancer cells (Huh-7.5 cells). Further, our study has confirmed that the ILs induce necrosis dependent cell death and that it is related to cell membrane damage. To understand the molecular mechanism of such an effect, the cellular membranes were mimicked as lipid monolayers formed at the air-water interface and then as lipid bilayer vesicles. The pressure area-isotherms measured from the monolayer have shown that the interaction of ILs with the lipid layer is energetically favourable. The addition of these ILs reduces the in-plane elasticity of the self-assembled molecular layer. Quasielastic neutron scattering data clearly indicate that ILs in liver lipid vesicles significantly affects the dynamics of the lipid, in particular, the lateral motion of the lipids. It has been concluded that the mammalian cell death induced by these ILs is due to the modulated structure and altered physical properties of the cellular membrane.

Re-entrant phase behavior of a concentrated anionic surfactant system with strongly binding counterions.

The phase behavior of the anionic surfactant sodium dodecyl sulfate (SDS) in the presence of the strongly binding counterion p-toluidine hydrochloride (PTHC) has been examined using small-angle X-ray diffraction and polarizing microscopy. A hexagonal-to-lamellar transition on varying the PTHC to SDS molar ratio (alpha) occurs through a nematic phase of rodlike micelles (Nc) --> isotropic (I) --> nematic of disklike micelles (N(D)) at a fixed surfactant concentration (phi). The lamellar phase is found to coexist with an isotropic phase (I') over a large region of the phase diagram. Deuterium nuclear magnetic resonance investigations of the phase behavior at phi = 0.4 confirm the transition from N(C) to N(D) on varying alpha. The viscoelastic and flow behaviors of the different phases were examined. A decrease in the steady shear viscosity across the different phases with increasing alpha suggests a decrease in the aspect ratio of the micellar aggregates. From the transient shear stress response of the N() and N(D) nematic phases in step shear experiments, they were characterized to be tumbling and flow aligning, respectively. Our studies reveal that by tuning the morphology of the surfactant micelles strongly binding counterions modify the phase behavior and rheological properties of concentrated surfactant solutions.

A comparative study of treatment outcome in younger and older patients with locally advanced oral cavity and oropharyngeal cancers treated by chemoradiation.

BACKGROUND: Evidence suggests that older patients with oral cavity and oropharyngeal cancers may behave differently from their younger peers. AIM: The aim of this study is to determine if there is difference in responses, survival, and toxicities between young patients (≤40 years of age) with oral cavity and oropharyngeal cancers and older patients (>40 years of age) treated with concurrent chemoradiation. MATERIALS AND METHODS: Sixty-one patients with unresectable, locally advanced oral cavity and oropharyngeal cancers received concomitant chemoradiation to a dose of 70 Gray in 35 fractions over 7 weeks with concomitant weekly cisplatin (40 mg/m2). These patients were then distributed in two arms. Arm-A patients having age ≤40 years and Arm-B patients having age >40 years, and the two arms were assessed for treatment outcome. RESULTS: The overall response rate (complete responders + partial responders) evaluated using response evaluation criteria in solid tumors criteria version 1.1 was equivalent in both groups (80.76% in Arm-A and 74.28% in Arm-B; P = 0.93). Older patients (>40 years) experienced more acute mucositis and xerostomia (P < 0.5); although not statistically significant, more acute skin and pharynx toxicities were also observed in this group. Higher late salivary gland toxicity (P < 0.5) was also seen in older patients; however, disease-free survival and progression-free survival were found to be similar in both groups. CONCLUSIONS: Older patients with locally advanced oral cavity and oropharyngeal cancers have similar response rates and survival as compared to their younger counterparts but may experience higher treatment-related toxicities.

A randomized controlled pilot study to compare capecitabine-oxaliplatin with 5-FU-leucovorin as neoadjuvant concurrent chemoradiation in locally advanced adenocarcinoma of rectum.

CONTEXT: Established as an adjuvant chemotherapy, CapeOX has recently been shown to have radiosensitizer property in a phase I and II studies, with appreciable downstaging and tolerable toxicities. AIMS: The study was designed to evaluate whether the capecitabine-oxaliplatin combination was superior to 5-fluorouracil (5-FU)-leucovorin as radiosensitizer for neoadjuvant chemoradiation in downstaging locally advanced rectal adenocarcinoma and to compare the toxicities between the two arms. SETTINGS AND DESIGN: Single institutional, double blinded, prospective, noncrossover, randomized control pilot study. SUBJECTS AND METHODS: In arm A (n = 21), patients received capecitabine (1,000 mg/m(2) daily) in twice dailydoseon days 1-14 and 25-38 and oxaliplatin (85 mg/m(2)) intravenous ( IV) over 2 h, on D1 and D29. In arm B (n = 21), patients received leucovorin (20 mg/m(2)) and 5-FU (350 mg/m(2)) from D1-5 and D29-33. Patient in both the arms received concurrent radiation (50.4 Gy in 28 #, in conventional fractionation of 1.8 Gy per fraction). Six to eight weeks after concurrent chemoradiation, patients underwent assessment and surgery with total mesorectal resection. Postoperatively, adjuvant chemotherapy with m-FOLFOX 6 of 4 months was given to all patients. STATISTICAL ANALYSIS USED: Chi-square test was used to compare categorical variables between the groups. RESULTS: Objective response rate (ORR) in arm A was 80.95% compared to arm B which had 66.66% (P = 0.3055). Pathological complete response (pCR) rate of arm A was comparable to arm B (23.8 vs 14.28%, P value = 0.6944). Surgery with R0 resection was possible in 80.95% cases of arm A compared to 66.66% cases of arm B (P = 0.4827). Grade III toxicities were quite comparable between two treatment arms. CONCLUSIONS: In terms of ORR, pCR rate, R0 resection, and toxicity profile; both the arms were comparable.

Demographic and clinical profile of patients with brain metastases: A retrospective study.

CONTEXT: Brain metastases are the most common type of intracranial neoplasm, with the total number outnumbering primary brain tumors by a ratio of 10:1 and occur in about 25% of cancer patients. However, controversies exist regarding demographic and clinical profile of brain metastases. AIMS: The purpose of this study was to analyze retrospectively the demographic and clinical profile of patients with brain metastases. SETTINGS AND DESIGN: Retrospective, single institutional study. MATERIALS AND METHODS: A retrospective study of 72 patients with brain metastasis was carried out from November 2010 to October 2012. The data pertaining to these patients was entered in a standardized case record form. These include History; clinical examination and other investigations including computed tomography/magnetic resonance imaging scan of the brain. STATISTICAL ANALYSIS: A statistical analysis was performed on the data collected using the MedCalc version 11. RESULTS: Brain metastases were more common in male and occur in 6(th) decade of life mostly. There was no relationship of occupation or socio-economic status with the incidence of brain metastases. Carcinoma lung was the most common primary giving rise to brain metastases followed by breast. Adenocarcinoma accounts for most common histology of the primary that give rise to metastases. Multiple metastases were more common than the single group. Supratentorial lesions were more common than infratentorial lesions. Among them, parietal lobe was the most common site of involvement. CONCLUSIONS: The present study highlights that the incidence of brain metastasis is common in elderly population and mostly due to primary lung. Adenocarcinoma was the most common histology of primary. Majority of lesions has been observed at parietal lobe.

Late nodal metastasis in early-stage node-negative oral cavity cancers after successful sole interstitial brachytherapy: an institutional experience of 42 cases in India.

PURPOSES: Brachytherapy, either alone or in combination with external irradiation, is a useful organ-preserving approach in the treatment of primary head and neck cancers. Treatment of regional nodal drainage area is not warranted in early-stage oral cavity cancers because T1N0 oral cavity cancers have less than 20% likelihood of nodal spread. We reviewed the records of interstitial brachytherapy cases of oral cavity cancers in our brachytherapy unit to assess the clinical outcome of the patients treated. METHODS AND MATERIALS: We tried to correlate the clinical outcome of the disease with different predictive factors for treatment outcome and to analyze statistically the role of these factors. RESULTS: Cases treated with combined external irradiation with interstitial brachytherapy included higher T stage, with greater risk for nodal spread, though initially node negative. As these were treated with microscopic dose for nodal clinical target volume, nodal recurrence was fewer (18.5%). On the contrary, although the early-stage (T1N0) oral cavity cancers that were treated with brachytherapy alone had initially a less than 20% chance of nodal metastasis, there was an increased risk up to 80% for late nodal metastasis after treatment. Tumor thickness >6mm (p=0.044) and need for a multiplanar implant (p=0.008) were found to be statistically significant risk factors for nodal recurrence. Other factors like high-grade tumors, ulcero-infiltrative lesions, implant of mobile tongue, and low hemoglobin, though relevant, were not found to be statistically significant. CONCLUSIONS: We recommend prophylactic nodal irradiation in addition to brachytherapy even for early-stage oral cancers treated with interstitial brachytherapy. Furthermore, the invasive procedure of interstitial brachytherapy causing a disruption of body's physiologic barrier to localize the disease is itself a probable risk factor for late nodal recurrence. Whether this, apart from the poor prognostic factors, causes increased chance of spread of a localized disease needs to be evaluated by a large prospective randomized study. This is needed to find out exactly the scenario where exclusive brachytherapy will be appropriate for treatment of early-stage oral cavity cancers.

Structure of mesh phases in cationic surfactant systems with strongly bound counterions: influence of the surfactant headgroup and the counterion.

We have studied the phase behavior of concentrated aqueous solutions of cetylpyridinium bromide (CPB) and sodium 3-hydroxy-2-naphthoate (SHN) using X-ray diffraction and polarizing optical microscopy. The phase behavior of this system is found to be very similar to that of the cetyltrimethylammonium bromide (CTAB)-SHN-water system, reported by us recently (Ghosh, S. K., et al. Langmuir, 2007, 23, 3606), but with the important difference that the mesh-like aggregates in the present system have square symmetry, instead of the hexagonal symmetry seen in the earlier case. A random mesh phase without long-range correlations of the in-plane structure, as well as an ordered mesh phase, where the mesh-like aggregates lock into a three-dimensional lattice, are observed, as in the CTAB-SHN-water system. The mesh-like aggregates do not form when the hydroxynaphthoate counterion is replaced by either salicylate or tosylate, which are also known to bind strongly to the surfactant micelle. Instead, the phase behavior of these ternary mixtures is akin to that of the CPB-water binary system; the only liquid crystalline phase observed being the hexagonal phase made up of cylindrical micelles. These results show the extreme sensitivity of the structure and stability of mesh phases to subtle changes in the interheadgroup interactions.