Neuroanatomical abnormalities related to dexamethasone exposure in survivors of childhood acute lymphoblastic leukemia

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex‐stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long‐term problems with learning may be related to residual posttreatment brain differences.     

Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with nonsmall cell lung cancer survival

The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing genotyping data from two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with nonsmall cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a singlelocus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression modeling of the PLCO dataset identified three potentially functional and independent SNPs (i.e., KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 (95% confidence interval [CI] = 0.79–0.94, p = 0.0007), 1.31 (1.16–1.47, p = 6.0 × 10⁻⁵) and 1.27 (1.12–1.44, p = 0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (p_trend < 0.0001 for OS and p_trend < 0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes.     

Increasing the rate of the hydrogen evolution reaction in neutral water with protic buffer electrolytes

Electrocatalytic generation of H₂ is challenging in neutral pH water, where high catalytic currents for the hydrogen evolution reaction (HER) are particularly sensitive to the proton source and solution characteristics. A tris(hydroxymethyl)aminomethane (TRIS) solution at pH 7 with a [2Fe-2S]-metallopolymer electrocatalyst gave catalytic current densities around two orders of magnitude greater than either a more conventional sodium phosphate solution or a potassium chloride (KCl) electrolyte solution. For a planar polycrystalline Pt disk electrode, a TRIS solution at pH 7 increased the catalytic current densities for H₂ generation by 50 mA/cm² at current densities over 100 mA/cm² compared to a sodium phosphate solution. As a special feature of this study, TRIS is acting not only as the primary source of protons and the buffer of the pH, but the protonated TRIS ([TRIS-H]⁺) is also the sole cation of the electrolyte. A species that is simultaneously the proton source, buffer, and sole electrolyte is termed a protic buffer electrolyte (PBE). The structure–activity relationships of the TRIS PBE that increase the HER rate of the metallopolymer and platinum catalysts are discussed. These results suggest that appropriately designed PBEs can improve HER rates of any homogeneous or heterogeneous electrocatalyst system. General guidelines for selecting a PBE to improve the catalytic current density of HER systems are offered.

Molecular hydrogen (H₂), a clean-burning and energy-dense fuel source, has been widely discussed as an attractive way to store intermittent energy from solar and wind through water electrolysis (1, 2). Current commercial electrolyzers can be separated into two categories based on their operating pH. The first are acidic polymer electrolyte membrane electrolyzers that work best with rare and expensive platinum-based electrocatalysts for the hydrogen evolution reaction (HER) (3). The second are strongly alkaline electrolyzers that suffer from caustic basic reaction conditions (4). Neutral pH conditions with inexpensive catalysts composed of Earth-abundant elements are a target for practical solar-to-hydrogen fuel devices due to lower cost and fewer safety concerns (5), but achieving fast rates with mild overpotentials under neutral conditions remains a challenge (6–12). In the pH range from 5 to 9, the electrocatalytic activity of platinum (Pt) itself does not conform to the expected thermodynamic potential shift with pH dependence of −59 mV/pH (13). This is due to the low concentration of the hydronium ion in this pH range and a transition to water as the primary reactant, which has a higher thermodynamic requirement for hydrogen evolution (13). Studies of electrocatalysts using buffers to maintain the pH in this range and ionic salts such as potassium chloride (KCl) to provide ionic strength to ensure high solution conductivity have shown that the buffer can aid the HER activity, presumably by acting as a proton donor (6, 14–18). To extend the scope of water-soluble electrocatalysts, biopolymers and bioinspired metallopolymer catalysts have also been studied (7, 12, 17–26). Bren and coworkers recently reported particularly enlightening studies of the effects of buffer pK_a and structure on the mechanism of the hydrogen evolution reaction for cobalt minienzymes (17, 18).We recently reported a new metallopolymer catalyst system built around a customized [2Fe-2S] catalyst site with a bridging aryldithiolato ligand which exhibits remarkable catalytic activity, air stability, and chemical stability (21). The electrocatalytic mechanism of the [2Fe-2S] catalysts with aryldithiolato ligands is known from previous studies and these catalysts operate at rates of 10⁵ s⁻¹ and faster (27–30). The readily synthesized and water-soluble metallopolymer composed of tertiary amine side-chain groups, PDMAEMA-g-[2Fe-2S] (Fig. 1), approached the current density of Pt operating in neutral water under the same conditions and matched the Faradaic yield (97 ± 3%) (21). Although the detailed structural and mechanistic causality of these profound improvements for these metallopolymer electrocatalysts remain subjects of study, the nature of this molecular system is ideal for studying solution effects on the HER reaction at neutral pH for complexes that are normally insoluble in water. In the course of characterizing these electrocatalysts, solutions containing tris(hydroxymethyl)aminomethane (TRIS) at pH 7 were discovered to be exceptionally advantageous to the catalytic rate. In contrast to the few previous studies of TRIS buffer with electrocatalysts (14, 15, 18), we utilized TRIS at a high concentration. At pH 7, TRIS is sufficiently in the cationic protonated form that additional electrolyte such as KCl is not needed for conductance. This important distinction from conventional studies allows TRIS to simultaneously play the roles of pH buffer, proton source, and sole electrolyte. There is precedence in employing buffers in a manner in which they are the sole electrolyte (7, 31–34). Referring to such species simply as a “buffer” or as an “electrolyte” is inadequate in representing the three functions including proton source. For the purposes of this paper we term a species that serves all three functions a protic buffer electrolyte (PBE). In the following discussion, a TRIS PBE solution is one in which [TRIS-H]⁺Cl⁻ is the sole electrolyte and the cation is a proton source, and a sodium phosphate PBE solution is one in which Na⁺[H₂PO₄]⁻ is the sole electrolyte and the anion is a proton source.Open in a separate windowFig. 1.(A) Depiction of the 2e⁻ electrocatalytic HER with POEGMA-g-[2Fe-2S] and/or PDMAEMA-g-[2Fe-2S] metallopolymers using TRIS or sodium phosphate protic buffer electrolytes at pH 7. (B) Image of POEGMA-g-[2Fe-2S] with MW = 14,216 grown in silico. The [2Fe-2S] active site is in the center of the polymer, blue represents the polymer backbone, and the rest are the oligo(ethylene glycol) side chains. See SI Appendix for the details of modeling and a larger image.One of the key unanswered questions for these new catalyst systems is whether the metallopolymer composition (i.e., amine side-chain groups) or the PBEs are more important to afford this outstanding catalytic activity. Herein we study the effects of PBEs by comparing the HER performances of a standard platinum catalyst and a [2Fe-2S] metallopolymer catalyst in TRIS PBE solutions, sodium phosphate PBE solutions, and a KCl electrolyte solution without a PBE. For this study, nonionic water-soluble metallopolymers were used, which were made using oligo(ethylene glycol) side-chain groups on the polymer to avoid the possibility of contributing effects of the protonated amino groups of PDMAEMA-g-[2Fe-2S] referred to earlier. The metallopolymer catalyst used in this work is designated as POEGMA-g-[2Fe-2S] (Fig. 1). We previously reported that this water-soluble metallopolymer was largely inactive for H₂ electrocatalysis at neutral pH in phosphate buffer (22). The current findings suggest that the use of electrolytes composed of inexpensive cationic organic proton donors can be readily applied to any homogeneous or heterogeneous electrocatalyst system as a facile means to enhance HER activity.