Melatonin and Metformin Failed to Modify the Effect of Dacarbazine in Melanoma

Lessons Learned

• Melatonin did not increase the efficacy of systemic chemotherapy in melanoma.
• Metformin did not increase the efficacy of systemic chemotherapy in melanoma.

     

Bioethics Consultation Practices and Procedures: A Survey of a Large Canadian Community of Practice

The literature fails to reflect general agreement over the nature of the services and procedures provided by bioethicists, and the training and core competencies this work requires. If bioethicists are to define their activities in a consistent way, it makes sense to look for common ground in shared communities of practice. We report results of a survey of the services and procedures among bioethicists affiliated with the University of Toronto Joint Centre for Bioethics (JCB). This is the largest group of bioethicists working in healthcare organizations in Canada. The results suggest there are many common services and procedures of JCB bioethicists. This survey can serve as a baseline for further exploration of the work of JCB bioethicists. Common practices exist with respect to the domains of practice, individual reporting relationships, service availability within business hours and the education and training of the bioethicist.     

The Relationship Between Vulnerable Attachment Style,Psychopathology, Drug Abuse,and Retention in Treatment Among Methadone Maintenance Treatment Patients

The relationship between vulnerable attachment style, psychopathology, drug abuse, and retention in treatment among patients in methadone maintenance treatment (MMT) was examined by the Vulnerable Attachment Style Questionnaire (VASQ), the Symptom Checklist-90 (SCL-90), and drug abuse urine tests. After six years, retention in treatment and repeated urine test results were studied. Patients with vulnerable attachment style (a high VASQ score) had higher rates of drug abuse and higher psychopathology levels compared to patients with secure attachment style, especially on the interpersonal sensitivity, anxiety, hostility, phobic anxiety, and paranoid ideation scales. Drug abstinence at baseline was related to retention in treatment and to higher rates of drug abstinence after six years in MMT, whereas a vulnerable attachment style could not predict drug abstinence and retention in treatment. Clinical Implications concerning treatment of drug abusing populations and methodological issues concerning the VASQ’s subscales are also discussed.     

Education is associated with reduction in racial disparities in kidney transplant outcome

In this study, we hypothesized that higher level of education might be associated with reduced racial disparities in renal transplantation outcomes. We used data from the United States Renal Data System (September 1, 1990–September 1, 2007) (n = 79 223) and analyzed two outcomes, graft loss and recipient mortality, using Cox models. Compared with whites, African Americans had increased risk of graft failure (HR, 1.48; p < 0.001) and recipient mortality (HR, 1.06; p = 0.004). Compared with recipients who graduated from college, all other education groups had inferior graft survival. Specifically, compared with college‐graduated individuals, African Americans who never finished high school had the highest risk of graft failure (HR, 1.45; p < 0.001), followed by high school graduates (HR, 1.27; p < 0.001) and those with some college education (HR, 1.18; p < 0.001). A similar trend was observed in whites. In African Americans (compared with whites), the highest risk of graft failure was associated with individuals who did not complete high school (HR, 1.96; p < 0.001) followed by high school graduates (HR, 1.47; p < 0.001), individuals with some college education (HR, 1.45; p < 0.001), and college graduates (HR, 1.39; p < 0.001). A similar trend was observed with recipient mortality. In sum, higher education was associated with reduced racial disparities in graft and recipient survival.     

Endocardial cushion defect associated with cor triatriatum sinistrum or supravalve mitral ring

Clinical and angiographic or autopsy data, or both, on three children with a subdivided left atrium (cor triatriatum) and an associated endocardial cushion defect are reviewed. (One child had ostium primum defect, and two had complete atrioventricular [A-V] canal.) A fourth patient demonstrates the difficulties in differentiating subdivided left atrium from supravalve mitral stenosis in the presence of an endocardial cushion defect. The clinical findings are greatly influenced by the endocardial cushion defect. A pressure gradient between the pulmonary wedge and (left or right) ventricular end-diastolic pressures in patients with an endocardial cushion defect indicates pulmonary venous obstruction and should alert one to the possibility of these combined lesions. The exact diagnosis is made with injections of angiographic contrast medium into the proximal and distal left atrial chambers, to document the respective relations of the pulmonary veins, left atrial appendage and A-V valves to these atrial chambers. All three patients with an endocardial cushion defect and a subdivided left atrium had an associated patent ductus arteriosus. The common association of subdivided left atrium with intracardiac, pulmonary venous and aortic anomalies is again demonstrated.     

Clinical results of drug eluting stents compared to bare metal stents for patients with ST elevation acute myocardial infarction

OBJECTIVE: To investigate the clinical outcomes in patients with ST segment elevation acute myocardial infarction (STEMI) treated with drug eluting stents (DES) versus a matched control group of patients with STEMI treated with bare metal stents (BMS). METHODS: This registry included 122 patients with STEMI undergoing primary coronary angioplasty with DES implantation at our institution. The control group consisted of 506 patients implanted with BMS, who were matched for age, infarct location, and diabetic status. The incidences of major adverse cardiac events (MACE) including target vessel/lesion revascularization (TVR/TLR) and stent thrombosis were assessed up to 12 months. RESULTS: Twelve months follow up showed a non-significant trend towards reduced deaths (3.3% versus 7.1%, P=0.1), significantly reduced recurrent MI (0.0% versus 6.1%, P=0.02), TVR (5.7% versus 15.2%, P=0.006) and TLR (2.5% versus 14.0%, P=0.004) events in the DES group as compared to BMS group. The composite incidences of MACE at 12 months follow-up was lower in the DES group (11.5%) as compared to the BMS group (21.3%, P=0.01). CONCLUSION: According to our experiences, the use of DES in STEMI is safe and effective as compared to BMS. DES was effective in reducing the incidence of restenosis outcomes and overall adverse cardiac events up to 12 months.     

Perylene bisbenzimidazole nonlinear dielectric material for energy storage

A novel perylene bisbenzimidazole comprising both donor and acceptor functional groups was designed, synthesized, and characterized. This structure exhibits potentially useful physical properties, including a nonlinear dielectric response to an increasing electric field. This material can be used in energy storage devices as the dielectric part of a capacitor. Energy storage devices based on film capacitors are targeting applications in a wide range of industrial, residential and transportation systems.

We synthesized and characterized an organic molecule which can serve as a unit for high-density energy storage.

Capacitors are among the simplest devices that store electrical energy and feature high charge–discharge rates, high power density, and a wide range of operating temperatures.¹ As a result, they have found use in many electronic devices and in numerous industrial applications. However, while capacitors feature high power density, they do not compete with the high gravimetric energy density of batteries, precluding their use as long-term energy storage devices. This disadvantage originates from the low polarizability of conventional dielectric materials found in modern industrial capacitors. We are developing new dielectric materials with high polarizability, high resistivity, and high breakdown voltage. These materials will widen the scope of capacitor applications to a variety of energy storage devices including transportation, industry, and residential applications.For traditional materials, dielectric polarizability is a constant value with stored energy sharing a linear relationship to the dielectric permittivity of the material. At high electric fields, however, many materials exhibit a nonlinear dielectric constant.² Commonly, these materials consist of highly polarizable molecules with electron-donating and/or electron-withdrawing groups on opposite sides of a large conjugated core. These groups can increase polarizability and further impart directionality to the delocalized electrons when an electric field is applied.Here we present the general structure for a non-linear dielectric chromophore, that we named dielectrophore, that would bring the combination of required properties into capacitors: high permittivity, resistivity, and breakdown strength, as well as good processability and mechanical flexibility.³ The main three components that build these properties are: the polyaromatic core, allowing π–π stacking within the material as well as high polarizability, donor and acceptor groups at each end of the conjugated core increasing the first hyperpolarizability, and insulating subunits that prevent current leakage within the capacitor (Fig. 1). In such structures, the cores are predominantly planar polycyclic molecular system which forms column-like supramolecular stacks by π–π interactions.Open in a separate windowFig. 1General representation of an ideal dielectrophore, such as 15.Perylene-3,4,9,10-tetracarboxylic acid diimides (PDIs) are among the most extensively used cores for studies of π–π stacking and columnar liquid crystalline structures. It is noteworthy that PDI-based molecules have been widely used as colorants and dyes, as well as chromophores for optoelectronic applications such as photovoltaics and organic field effect transistors. This is due to the combination of their optoelectronic properties, such as large extinction coefficients, high fluorescent quantum yields, strong electron-accepting ability (N-type semiconductors), and high thermal and chemical stability.⁴ Most of these properties originate from the delocalization of the π electrons of the PDI''s. In addition, the modular structure and straightforward synthesis of PDI-based molecules streamline the modification of their structures, which helps to bring all the required properties of our dielectrophores.Our theoretical studies demonstrated that linear polarizability of the PDIs can be strongly increased by transforming the diimide functions into the more conjugated benzimidazole derivatives and adding donor (NEt₂) and acceptor groups (NO₂) at the opposite sides of a molecule.⁵ Considering the predicted design, we propose molecule 15 as our target molecule (Fig. 1). Long alkyl chains are added via phenyl linkers at both sides of the molecule and bring significant impact into the resistivity of the potential capacitor and help with processability during the synthetic manipulations and film coating.One of the main advantages of 15 is the modularity of its synthesis, which can be performed as a step-wise addition of two substituted o-phenylenediamines to 13 (Scheme 1). 13 was synthesized according to a modified procedure reported by Xiao and co-workers (outlined in Scheme 1).⁶ In our synthesis, 3 is accessed through a 2-step derivatization of catechol (1) through an alkylation followed by a C–H activated borylation.⁷ The electron-acceptor diamine (7) was synthesized from 2,5-dinitroaniline (4) via bromination with NBS, followed by Suzuki coupling with 6, and further reduction of one of the nitro groups with ammonium sulfide. The electron donating diamine (12) was synthesized from 3-bromo-2,5-difluoronitrobenzene (8) via nucleophilic aromatic substitution at room temperature, followed by Suzuki coupling with 3 to isolate 10. A nucleophilic aromatic substitution with benzylamine at elevated temperature yields 11 and a deprotection/reduction using Pd(OH)₂/C and H₂ at 55 psi afforded 12. 14 was obtained in two steps by stirring diamine 7 with 13 in molten imidazole at 140 °C for 12 hours then further treating the product with an excess of para-toluenesulfonic acid in toluene at 100 °C to afford 14 in 37% overall yield (Scheme 1).Open in a separate windowScheme 1Synthesis of 15.15 was made through the condensation of mono-anhydride 14 with diamine 12 with the presence of zinc acetate in quinoline at 140 °C for 12 hours. Upon precipitation into methanol, 15 was isolated as a dark purple solid. It is important to mention that reactions of 13 with 7 and then 14 with 12 are likely not regioselective, even though steric factors favour the formation of the isomers 15a and 15b (Scheme 2) with donor/acceptor groups located farther from carboxamide group, especially in the case of the bulkier diethylamino group. Indeed, six additional isomers may be present, in addition to 15a and 15b (15c–h, see ESI^†). Column chromatography to separate these regioisomeric mixtures is shown to be quite challenging.⁸ Considering our theoretical studies, that demonstrated both syn- and anti-isomers to have similar predicted polarization values, separation of individual isomers is unnecessary.⁵Open in a separate windowScheme 2Main isomers of 15.15 was characterized with UV-vis and FTIR spectroscopic techniques and molecular weight was confirmed through mass spectrometry (see ESI^†). FTIR of 15 shows the absence of the anhydride carbonyl stretches of 14 at 1769 and 1732 cm⁻¹ respectively and the emergence of benzimidazole stretches at 1691, 1592, and 1573 cm⁻¹.⁹¹H NMR of 15 in 100% CDCl₃ initially exhibit very broad signals, but when 10% dTFA is added this aggregation is broken up (see ESI^†). The formation of the benzimidazole extends the length of conjugation considerably, this transformation can be clearly observed in the UV-vis spectra where the λ_max shifts from 523 nm for 13 to 555 nm for 14 (ESI^†). The λ_max shifts even further towards the near infrared region (752 nm) upon addition of the donor block (12) and making 15 (Fig. 2A). The drastic broadening of the band from 500 to 900 nm for 15 is caused by the extended conjugation, the formation of π–π-aggregates in the solution and the presence of a mixture of isomers,^8a as well as intramolecular charge transfer (ICT) in this push–pull system.¹⁰ The UV-vis spectrum in chloroform was predicted using a B3LYP/6-31H level of theory and compared with the experimental data (see ESI^†). The computed spectrum identifies three major bands at 409, 552, and 850 nm, respectively, in some agreement with the observed λ_max at 395, 525, and 752 nm (ESI^†). 15 was then cast into films on the Indium–Tin–Oxide (ITO)/glass substrate (see ESI^†) and charged through corona poling to test its nonlinear behaviour in the presence of an electric field.Open in a separate windowFig. 2(A) UV-vis absorption spectra of intermediates 13 (solid red), and 14 (dashed green), and final perylene-bisbenzimidazole 15 (dash-dot blue) (0.05 mg mL⁻¹ in CHCl₃). (B) Corona charging capacitor experiment of films cast from polypropylene (PP, dash black) and 15 (dash-dot blue).In corona poling, a sharp corona tip is charged up to several kilovolts until the electric breakdown of surrounding atmosphere occurs and the positive or negative ions are deposited on the film surface.¹¹ With this approach, a large electric field necessary to study the nonlinear response of the material is achieved. Once charge is deposited we used a Kelvin probe to measure the surface potential and its dependence on the amount of deposited charges, which can be determined by measuring the current from the bottom ITO electrode to the ground. This current is directly proportional to the voltage of the corona electrode, as expected, and is controlled by the corona current setting. It is then a simple calculation to convert the time under the corona charge deposition into the charge density on the top of the film. In our experiment, we use the current of 10⁻⁵ A and the area of the film is 11.5 × 6 cm².The results of the corona experiment are shown in Fig. 2B for the 2.165 μm thickness film of 15 and 6 μm polypropylene (PP) thin film for the comparison. PP is a common material used as a dielectric in many high voltage capacitors and shows a usual linear relationship between increasing charge density and a growing electric field (Fig. 2B). The dielectric constant of PP is estimated through this approach to be 2.9, close to the tabulated value.¹² When 15 is exposed to the same conditions, we observe a nonlinear voltage saturation at an electric field of 40 V μm⁻¹. We can conclude that in such nonlinear regime the deposition of additional charge leads to the increase of the polarization, not to the increase of the electric field. It should be emphasized that in PP films the electric breakdown occurs after about 10 seconds of the charge deposition, while 15 can sustain up to 5 hours at the same conditions. Correspondingly, the energy stored in the capacitor based on our molecule would be larger than that of the polypropylene-based capacitor by several orders of the magnitude.     

Epidermal growth factor stimulation of DNA synthesis is potentiated by compounds that inhibit its clustering in coated pits

We have used inhibitors of receptor-mediated endocytosis to investigate the mechanism and function of epidermal growth factor uptake by cultured cells. When rhodamine-labeled epidermal growth factor is bound to cell surface receptors on confluent monolayers of BALB/c 3T3 cells, it rapidly collects in cell surface clusters and is internalized. The clustering of occupied receptors requires Ca(2+) and is inhibited by primary alkylamines; both of these properties are shared by the enzyme transglutaminase (R-glutaminyl-peptide:amine gamma-glutamyl-yltransferase, EC 2.3.2.13). In Chinese hamster ovary cell extracts, methylamine inhibits 25-50% of the transglutaminase activity with a K(i) of 0.2 mM, and it inhibits the remaining transglutaminase activity with a K(i) of 20 mM. Clustering is almost completely inhibited by 10 mM methylamine. The polypeptide antibiotic bacitracin inhibits clustering of rhodamine-labeled epidermal growth factor or alpha(2)-macroglobulin at 0.7 mM, and it inhibits approximately 40% of the transglutaminase activity in Chinese hamster ovary cells with a K(i) of 0.03 mM. Fluorescent ligands bound to cell surface receptors in the presence of bacitracin form clusters within 30 min after bacitracin is removed from the culture medium. These results indicate that a transglutaminase-like enzyme may be required for the clustering and subsequent internalization of occupied receptors. The effects of 10 mM methylamine and 0.7 mM bacitracin on epidermal growth factor stimulation of DNA synthesis were examined. The stimulation of DNA synthesis by epidermal growth factor was increased 2- to 7-fold in the presence of methylamine or bacitracin. Alone, methylamine or bacitracin increased DNA synthesis 1.1- to 3-fold. The stimulation of DNA synthesis resulting from the simultaneous presence of the hormone and the clustering inhibitor was always greater than the sum of the stimulations produced by the hormone and the clustering inhibitors alone. The potentiation of epidermal growth factor activity by clustering inhibitors suggests that the hormone acts at the cell surface. We propose that rapid internalization of occupied receptors via coated pits may be a mechanism to limit the response to hormones.