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Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t1/2= 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10–6M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]−anion possessed a high degree of symmetry, and the La3+ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]−complex also demonstrated a superb thermodynamic stability (log K[La(py4pa)]–∼ 20.33, pLa = 21.0) compared to those of DOTA (log K[La(DOTA)]–∼ 24.25, pLa = 19.2) or H2macropa (log K[La(macropa)]–= 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitroserum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivostability and tumor specificity.

Potentially nonadentate (N5O4) bifunctional chelator p-SCN–Bn–H4neunpa and its immunoconjugate H4neunpa–trastuzumab for 111In radiolabeling are synthesized. The ability of p-SCN–Bn–H4neunpa and H4neunpa–trastuzumab to quantitatively radiolabel 111InCl3at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In3+, Bi3+, and La3+resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both 111In complexes to have high stability over 5 days. Mouse biodistribution of [111In][In(p-NO2–Bn–neunpa)]−, compared to that of [111In][In(p-NH2–Bn–CHX-A″–diethylenetriamine pentaacetic acid (DTPA))]2–, at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates 111In-neunpa–trastuzumab and 111In–CHX-A″–DTPA–trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of 111In-neunpa–trastuzumab compared to that of 111In–CHX-A″–DTPA–trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN–Bn–H4neunpa to be a promising chelator for 111In (and other radiometals) with high in vitro stability and also show H4neunpa–trastuzumab to be an excellent 111In chelator with promising biodistribution in mice.

Zirconium-89 (89Zr) is a suitable radionuclide for positron-emission tomography (PET) of long-circulating targeting vectors such as monoclonal antibodies (mAbs). Due to stability concerns for the most widely used 89Zr-chelating agent desferrioxamine B (DFO) in preclinical studies, alternative 89Zr-chelators are currently being developed. We recently reported on the first tetrakis(3-hydroxy-4-pyridinone) (3,4-HOPO) ligand THPN, which was identified as a promising 89Zr-chelator. In this study, we aimed to further explore this octadentate chelate in vitro and in vivo. The [ZrIV(THPN)] thermodynamic stability was quantified in solution titration studies, which revealed one of the highest formation constants reported for a zirconium chelate (log βML50.3(1), pM = 42.8). Solution stabilities with iron(III) were also exceptionally high and can compete with some of the strongest FeIII-chelates. A first bifunctional derivative of the octadentate ligand, p-SCN-Bn-THPN, was then produced in a multistep synthesis. To assess and compare the long-term 89Zr complex stability, bifunctional THPN, as well as the literature chelators p-SCN-Phe-DFO and p-SCN-Phe-DFO*, were conjugated to the high-molecular weight (800 kDa) polymeric carrier hyperbranched polyglycerol (HPG). The functionalized HPGs were radiolabeled with 89ZrIV, and the integrity of the radioconjugates was assessed over several days in vitro and in vivo. While all three radioconjugates remained >95% intact over 5 days in human plasma, the in vivo study in healthy mice revealed higher physiologic stability of the DFO and DFO* radiochelates over bifunctional THPN conjugates. This was evidenced by increased bone uptake of osteophilic 89ZrIVfor THPN. This finding contrasts with the exceptionally high thermodynamic stability of the chelate and suggests either a kinetic or metabolic lability, or may stem from coordinative changes due to the covalent conjugation of the 89Zr-THPN radiochelate as suggested by density functional theory (DFT) calculations. These important findings inform the design of next generation 3,4-HOPO chelates with the aim of improving the physiologic stability. This study furthermore demonstrates how HPG can be used as a robust carrier tool to assess and compare the long-term in vivo stability of radiochelates.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2009.01.019 Byline: Julie-Anne Rousseau, Karine Girard, Lucile Turcot-Lemay, Nancy Thomas Keywords: cesarean; pain; skin closure; staples; subcuticular sutures Abstract: We sought to compare postoperative pain according to the skin closure method (subcuticular sutures vs staples) after an elective term cesarean section. Author Affiliation: Department of Obstetrics and Gynecology, Laval University, Quebec, QC, Canada Article History: Received 23 November 2008; Revised 21 December 2008; Accepted 20 January 2009 Article Note: (footnote) Cite this article as: Rousseau J-A, Girard K, Turcot-Lemay L, et al. A randomized study comparing skin closure in cesarean sections: staples vs subcuticular sutures. Am J Obstet Gynecol 2009;200:265.e1-265.e4. , Supported by a Grant from the Jeanne et Jean-Louis Levesque Foundation for Maternal-Fetal Medicine Research.

Wastes from lignocellulosic materials, especially hemicellulose, are extremely promising resources to produce fuels from renewable raw materials. Furfural, resulting from the depolymerization of hemicellulose, is often considered as an extremely interesting platform molecule. Particularly, new biofuels containing molecules with 8 and 13 carbon atoms can be produced from aldol condensation of furfural and acetone followed by a deoxygenation reaction. In this work, several magnesium hydroxide fluorides MgF2−x(OH)xwere prepared by a sol–gel method with various F/Mg ratios (0 to 2) at 100 °C. All solid samples were fully characterized by several techniques (nitrogen adsorption–desorption, TEM, IR, XRD and ICP). MgF2−x(OH)xwere mainly composed of an intimate mixture of MgF2and Mg(OH)2−x(OCH3)xand exhibited both acid–base properties and high surface areas. From CO2adsorption experiments, a basicity scale corresponding to basic sites with moderate strength was established: MgF1.5(OH)0.5> MgF(OH) ∼ MgF1.75(OH)0.25> MgF0.5(OH)1.5> Mg(OH)2 MgF2. It was proposed that the presence of fluorine allowed stabilization of the basic sites with moderate strength at ambient atmosphere. The aldol condensation of furfural and acetone was carried out under mild reaction conditions (50 °C, Patm) over MgF2−x(OH)x. These catalysts were involved in this reaction without using a classical activation step for basic solid catalysts, which constitutes a major advantage of energy conservation and thus, economic efficiency. The solid with a F/Mg ratio equal to 1.5 (MgF1.5(OH)0.5) exhibited the highest activity, the furanic dimer (1,5-di(furan-2-yl)penta-1,4-dien-3-one) being the main product. A good correlation between the catalytic activity and the basicity scale was highlighted. Based on these results, the nature of active sites was proposed: a combination of a Lewis acid site (coordinatively unsaturated metal site) in the vicinity of a basic site (hydroxyl groups of Mg(OH)2−x(OCH3)x). The effect of the furfural/acetone ratio on the catalytic properties of MgF1.5(OH)0.5was also investigated.

The aim of this work was to obtain an in-depth understanding of the U(VI) adsorption mechanism over amino-functionalized mesoporous silica SBA-15 and highlights its high efficiency in aqueous media for U(VI) removal and preconcentration. The samples were synthesized and functionalized by both grafting and co-condensation methods, using different alkyl-substituted amine groups and were characterized using X-ray diffraction, N2physisorption, Fourier transform infrared spectroscopy, and elemental C–H–N–S analyses. The properties for U(VI) adsorption were evaluated under discontinuous conditions, with the determination of the effect of several parameters (initial pH, contact time, initial U(VI) concentration, functionalization method, and organic moiety composition). U(VI) adsorption over grafted materials reached equilibrium at around 30 min, with a maximum adsorption capacity of 573 mgU·gads–1for the most efficient material at its optimal adsorption pH (equal to 6) at 20 °C. Functionalized materials by grafting exhibit better adsorption capacities than co-condensed samples because of higher function surface density and function availability. U(VI) adsorption mechanisms were also studied by measuring the electrophoretic mobilities of the particles, aqueous U(VI) speciation, in situ attenuated total reflection infrared and Raman spectroscopies, and transmission electron microscopy analysis. U(VI) adsorption occurred through the formation of an inner sphere complex. The localization of adsorbed U(VI) has also been determined inside of the mesopores, with the formation of several particles on the nanometer scale, in the size of U-hydroxy phases. Besides, the study of the reusability of amino-functionalized SBA-15 by applying adsorption–desorption cycles was also conducted. The adsorption capacity of the material remains stable for at least four adsorption–desorption cycles without any noticeable capacity decrease.

This work reports the synthesis of Co3O4particles that can be used as effective electrode materials for both the oxygen reduction (ORR) and evolution (OER) reactions. The development of such catalysts, free from precious group metals and capable of decreasing overpotentials in fuel cells, metal–air batteries, and water electrolyzers, also requires stable supporting and conducting substrates in order to deposit low metal oxide loadings. This challenging approach led us to prepare Co3O4materials on graphene-based composites more stable than common used Vulcan carbon. Co3O4particles synthesized from a solvothermal method were thereby deposited onto reduced graphene oxide (RGO) and N-doped reduced graphene oxide (NRGO) prepared from the Hummers method. The structural properties and surface composition of the different materials characterized by X-ray diffraction, transmission electron microscopy, and X-ray induced photoelectron spectroscopy measurements were combined to cyclic voltammetry experiments for revealing the charge transfer from cobalt to nitrogen, which greatly affects the charge acceptance of the surface Co atoms. Electrochemical measurements provided sound evidence of active and stable Co3O4catalysts toward the ORR and OER.

Background:The COVID-19 pandemic disproportionately affected populations served by Federally Qualified Health Centers (FQHCs), with high morbidity and mortality rates in ethnic minority older adults. In response to this pandemic, academic geriatric medicine teams through federally funded Geriatric Workforce Enhancement Program (GWEP) with FQHC partnership implemented new initiatives to improve the care for vulnerable older adults. Objectives:To describe how four FQHC/GWEP teams collaborated in caring for diverse communities of older adults during the pandemic. Methods:Four GWEPs have addressed pandemic response efforts with their respective FQHC partners. These collaborations to meet the increasing numbers of older adults seeking services, and the rising disparities exacerbated during the pandemic are delineated. Results:FQHC/GWEP partnerships enabled access to care, whether in-person or virtually to serve unmet needs of underserved older adults during the pandemic. Partnerships promoted COVID-19 education, testing, and vaccinations. Most FQHCs faced severe staffing shortages, and the digital divide challenged patients with barriers. GWEPs provided direct care, created educational materials, and developed telehealth programs. These partnerships addressed social determinants of health gaps caused by the pandemic. Conclusion:The findings demonstrate that strong partnerships between GWEPs and FQHCs mitigate health inequities for vulnerable ethnic minority and rural older adults during pandemic crises.

Seminal papers have highlighted the promoting effect of gold when associated with other metals. There is still a lack of information about the origin of the exceptional electrochemical performances of gold-based nanostructures, known so far as one of the most active electrocatalysts for glucose-based energy conversion devices. In this report, we examined the correlation between the electrocatalytic properties and the surface composition on a line-up of Au-based nanostructures: gold-palladium, gold-platinum binaries, and gold-palladium-platinum ternaries from the so-called Bromide Anion Exchange (BAE) method. BAE enables to obtain carbon supported nanocrystals having high Miller indices. These truncated octahedron nanocrystals present twins as well as (110) facets. Both X-ray photoelectron spectroscopy (XPS) and electrochemical characterizations have shown that the surface of the multimetallic nanomaterials contains less atoms of gold. The most exposed platinum and palladium enable improving glucose electrooxidation reaction kinetics at low electrode potentials. Additionally, XPS measurements have shown that the binding energy (BE) of either Pd or Pt shifts towards low values when associated with Au, indicating strong electronic interactions between the different elements in the multimetallic nanomaterials. These properties have led to improved catalytic performances when tested for CO stripping experiments and glucose (potential fuel) electrooxidation reaction in alkaline medium.

A bimetallic cobalt molybdenum sulfide (Co0.5Mo0.5Sx) material was studied as candidate electrocatalyst to replace platinum-based cathode for HER reaction in alkaline media. The Co0.5Mo0.5Sxwas obtained from a hydrothermal synthesis methodology employing sodium diethyldithiocarbamate as sulfurizing agent, a non-conventional compound. The recovered sulfide material was physicochemically characterized by XRD, Raman spectroscopy, TEM and XPS measurements. Analogous monometallic sulfides were also synthesized to compare their HER activities to that of Co0.5Mo0.5Sx. Such electrochemical characterization was performed by the application of polarization and EIS analyzes in 1 M KOH. An evident synergistic effect emerged in the bimetallic sulfide and it was associated with the design of a catalyst less susceptible to air-oxidation added to the roles performed by cobalt- and molybdenum-based species in the HER mechanism. Finally, a physical mixture of Co0.5Mo0.5Sxand Carbon Vulcan was prepared aiming to enhance the electronic conductivity of the electrode. As result, an overpotential of 131 mV was requested to achieve −10 mA cm−2. In addition, to achieve −200 mA cm−2, this electrode only needed an overpotential 66 mV higher than the one necessary for the benchmarking 40% Pt/C electrocatalyst.

The photocurrent response of TiO2nanoparticles synthesized via the sol–gel process was studied in the presence of methanol, ethanol, and isopropanol. The nanocrystalline nature of photoelectrodes showed an important photocurrent in the presence of alcohol following the order methanol ≈ ethanol > isopropanol > H2O. This process mimics the photoelectrochemical response, and therefore a correlation of the photodeposition process of platinum nanoclusters on TiO2particles in the presence of alcohol molecules was devised. The photodeposition mechanism of platinum nanoislands at the surface of a nanocrystalline TiO2powder is discussed in the light of the photoelectrochemical results.

The physicochemical properties of noble metal such as gold strongly depend on their size, shape, and their surface structure composition. Gold NPs have been studied in electrocatalysis due to their unexpected activity toward the oxidation of organics. The chemical reactions studies on a well-defined shape provide fundamental data on the surface reactivity for understanding and designing novel catalytic materials. Therefore, different gold nanorods (GNRs) were synthesized by chemical growth process. The UV–vis spectroscopy and transmission electron microscopy measurements confirmed their well-defined shape and size distribution. Moreover, the under-potential of lead (UPD), which is a sensitive electrochemical surface characterization tool, has been used to assess GNRs crystallographic structure information. Additionally, the UPD of lead reveals that their crystallographic facets are affected by their growth process. Most importantly, the interaction between GNRs surface and the remaining capping agent (CTAB) adsorbed after cleaning process has a high effect on the lead deposition and also leads to a decrease in the electrochemical activity of GNRs. The activity of different GNRs toward glucose oxidation was also investigated. The correlation between the activity of these materials toward this reaction and their surface structure was established. It shows an enhancement of the electroactivity in the presence of (100) facets.

Neuropsychological problems occurrence varies among childhood cancer survivors, and associated risk factors have not been fully deciphered. We wanted to study the role of genetic variants in behavioral problems in this population.

A personal narrative is presented which explores the author's experience of how she gave her personal best as a women's basketball coach.

Asparaginase is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia. Asparagine synthetase (ASNS) and the basic region leucine zipper activating transcription factor 5 (ATF5) and arginosuccinate synthase 1 (ASS1) have been shown to mediate the antileukemic effect of asparaginase and to display variable expression between leukemia cells that are resistant and sensitive to treatment. Fourteen polymorphisms in the regulatory and coding regions of these genes were investigated for an association with acute lymphoblastic leukemia outcome. Lower event-free survival (EFS) was associated with ATF5T1562C, tandem-repeat ASNSpolymorphism, derived haplotype, and ASS1G1343T and G34T substitutions (P≤ .03). Associations were limited to patients who received Escherichia coliasparaginase. Variations that sustained correction for multiple testing (ATF5T1562C, P= .005; ASNStandem-repeat and related haplotype, P≤ .01) were subsequently analyzed in the replication cohort. The E coli–dependent association of the ATF5T1562 allele with reduced EFS was confirmed (P= .01). A gene-reporter assay showed that the haplotype tagged by T1562 had higher promoter activity (P≤ .01). The remaining regulatory polymorphisms also appeared to affect ATF5 function; 2 additional high-activity haplotypes were identified (P≤ .02) and were further corroborated by quantitative mRNA analysis in lymphoblastoid cell lines. The ATF5-regulated increase in ASNS expression in response to more efficacious E coli–induced asparagine depletion may explain our observed results.

Asparaginase is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia. Asparagine synthetase (ASNS) and the basic region leucine zipper activating transcription factor 5 (ATF5) and arginosuccinate synthase 1 (ASS1) have been shown to mediate the antileukemic effect of asparaginase and to display variable expression between leukemia cells that are resistant and sensitive to treatment. Fourteen polymorphisms in the regulatory and coding regions of these genes were investigated for an association with acute lymphoblastic leukemia outcome. Lower event-free survival (EFS) was associated with ATF5 T1562C, tandem-repeat ASNS polymorphism, derived haplotype, and ASS1 G1343T and G34T substitutions (P ≤ .03). Associations were limited to patients who received Escherichia coli asparaginase. Variations that sustained correction for multiple testing (ATF5 T1562C, P = .005; ASNS tandem-repeat and related haplotype, P ≤ .01) were subsequently analyzed in the replication cohort. The E coli–dependent association of the ATF5 T1562 allele with reduced EFS was confirmed (P = .01). A gene-reporter assay showed that the haplotype tagged by T1562 had higher promoter activity (P ≤ .01). The remaining regulatory polymorphisms also appeared to affect ATF5 function; 2 additional high-activity haplotypes were identified (P ≤ .02) and were further corroborated by quantitative mRNA analysis in lymphoblastoid cell lines. The ATF5-regulated increase in ASNS expression in response to more efficacious E coli–induced asparagine depletion may explain our observed results.

Mycobacterium tuberculosis group I truncated hemoglobin trHbN catalyzes the oxidation of nitric oxide (•NO) to nitrate with a second-order rate constant k ≈ 745 μM−1 s−1 at 23°C (nitric oxide dioxygenase reaction). It was proposed that this high efficiency is associated with the presence of hydrophobic tunnels inside trHbN structure that allow substrate diffusion to the distal heme pocket. In this work, we investigated the mechanisms of •NO diffusion within trHbN tunnels in the context of the nitric oxide dioxygenase reaction using two independent approaches. Molecular dynamics simulations of trHbN were performed in the presence of explicit •NO molecules. Successful •NO diffusion from the bulk solvent to the distal heme pocket was observed in all simulations performed. The simulations revealed that •NO interacts with trHbN at specific surface sites, composed of hydrophobic residues located at tunnel entrances. The entry and the internal diffusion of •NO inside trHbN were performed using the Long, Short, and EH tunnels reported earlier. The Short tunnel was preferentially used by •NO to reach the distal heme pocket. This preference is ascribed to its hydrophobic funnel-shape entrance, covering a large area extending far from the tunnel entrance. This funnel-shape entrance triggers the frequent formation of solvent-excluded cavities capable of hosting up to three •NO molecules, thereby accelerating •NO capture and entry. The importance of hydrophobicity of entrances for •NO capture is highlighted by a comparison with a polar mutant for which residues at entrances were mutated with polar residues. A complete map of •NO diffusion pathways inside trHbN matrix was calculated, and •NO molecules were found to diffuse from Xe cavity to Xe cavity. This scheme was in perfect agreement with the three-dimensional free-energy distribution calculated using implicit ligand sampling. The trajectories showed that •NO significantly alters the dynamics of the key amino acids of Phe62(E15), a residue proposed to act as a gate controlling ligand traffic inside the Long tunnel, and also of Ile119(H11), at the entrance of the Short tunnel. It is noteworthy that •NO diffusion inside trHbN tunnels is much faster than that reported previously for myoglobin. The results presented in this work shed light on the diffusion mechanism of apolar gaseous substrates inside protein matrix.

Proton magnetic resonance spectroscopy (1H MRS) was used to evaluate changes in cerebral metabolites in 13 patients with Cushing's syndrome (including seven with pituitary corticotroph adenomas and six with primary adrenal disease) as compared to 40 normal subjects. Data were recorded in the frontal, thalamic and temporal areas; quantification of the MRS signals demonstrated a statistically significant decrease of the Cho/Cr ratio in the frontal and thalamic areas but not in the temporal area for patients with Cushing's syndrome. The largest decrease in Cho/Cr was measured in the thalamic area of patients with a Cushing's syndrome secondary to an adrenal disease. No statistically significant changes in the NAA/Cr ratio were measured in any of the areas studied. These results suggest that the quantification of choline levels could be helpful for monitoring the cerebral metabolite alterations in patients with hypercortisolism. Copyright © 1999 John Wiley & Sons, Ltd.

Classical osteogenesis imperfecta (OI) is an inherited rare brittle bone disease caused by dominant mutations in the COL1A1or COL1A2genes, encoding for the α chains of collagen type I. The definitive cure for the disease will require a gene therapy approach, aimed to correct or suppress the mutant allele. Interestingly, individuals lacking α2(I) chain and synthetizing collagen α1(I)3homotrimers do not show bone phenotype, making appealing a bone specific COL1A2silencing approach for OI therapy. To this aim, three different Col1a2-silencing RNAs (siRNAs), −3554, −3825 and −4125, selected at the 3′-end of the murine Col1a2transcript were tested in vitroand in vivo. In murine embryonic fibroblasts Col1a2-siRNA-3554 was able to efficiently and specifically target the Col1a2mRNA and to strongly reduce α2(I) chain expression. Its efficiency and specificity were also demonstrated in primary murine osteoblasts, whose mineralization was preserved. The efficiency of Col1a2-siRNA-3554 was proved also in vivo. Biphasic calcium phosphate implants loaded with murine mesenchymal stem cells were intramuscularly transplanted in nude mice and injected with Col1a2-siRNA-3554 three times a week for three weeks. Collagen α2 silencing was demonstrated both at mRNA and protein level and Masson's Trichrome staining confirmed the presence of newly formed collagen matrix. Our data pave the way for further investigation of Col1a2silencing and siRNA delivery to the bone tissue as a possible strategy for OI therapy.

Mesoporous Co3O4mixed CoO onto reduced graphene oxide (rGO) nanocomposites were obtained by an easy surfactant-free synthesis using urea as hydrolyzing agent. This route enabled nanomaterials presenting tuned morphology, surface composition and oxide-rGO interactions as revealed by the different characterization techniques. Indeed, nanostructures varied from broom-like, chrysanthemum-like to micro-sized sheet-like morphologies. The amount of Co3O4phase was shown to be gradually rising as the urea amount increases being always higher at the surface than in the bulk. Different oxide-rGO interactions have also been demonstrated, suggesting that high amounts of urea cause a decrease in the size of the nanoparticles and limit their superposition. The catalysts prepared at high urea concentrations showed more exposed electroactive surface and enhanced activity as bifunctional oxygen electrocatalysts. Furthermore, the most active nanocomposite exhibited remarkable stability, making it a very promising candidate for the elaboration of a stable and truly reversible air electrode in alkaline media.

Off Label Use: Hemin recognized therapeutic indication is the treatment or prevention of acute attack of hepatic porphyria.