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The metabolism of (177)Lu-AMBA (AMBA = DO3A-CH(2)CO-G-(4-aminobenzoyl)-QWAVGHLM-NH(2)), a radiotherapeutic compound in clinical development that binds to GRP and NMB receptors, was studied in vitro (mouse, rat and human plasma, mouse kidney homogenate) and in vivo (by analysis of mouse and rat plasma and urine following IV injection of (177)Lu-AMBA). The primary metabolites were Lu-DO3A-CH(2)CO-G-Abz4-R, where R = -Q-OH (A), -QW-OH (B), and -QWAVGH-OH (C). Minor amounts of (D) where R = -QWAVGHLM-OH and (E) -QWAVGHL-OH were also observed. Clearance of (177)Lu-AMBA and of radioactivity from mouse and rat blood was rapid in vivo. In mouse and rat urine, only metabolites Lu-A and Lu-B were found-no parent drug was excreted. Unmetalated ligands and (nat)Lu and (177)Lu complexes for Lu-AMBA metabolites A-E were synthesized, characterized by HPLC and MS, and used to perform in vitro competition and direct binding studies on GRP receptor-positive PC-3 (human prostate) cancer cells. Biodistribution studies with (177)Lu-labeled metabolites A-E were performed in PC-3 tumor-bearing mice and the results compared with intact (177)Lu-AMBA. IC(50) values for unmetalated metabolite ligands A-E were >400 nM in PC-3 cells in competition binding studies against (177)Lu-AMBA. No direct binding to PC-3 cells was observed with (177)Lu-labeled A-C, confirming IC(50) results. (177)Lu-labeled metabolites A-E showed no uptake in GRP-receptor positive tumor or pancreas in PC-3 tumor bearing mice. All metabolites were rapidly excreted via the renal route (approximately 78-87%) within 1 h. These results demonstrate that the tumor uptake observed with (177)Lu-AMBA is due to parent drug and not due to any of its identified metabolites.

T his paper studies the effect of online product reviews on different players in a channel structure. We consider a retailer selling two substitutable products produced by different manufacturers, and the products differ in both their qualities and fits to consumers' needs. Online product reviews provide additional information for consumers to mitigate the uncertainty about the quality of a product and about its fit to consumers' needs. We show that the effect of reviews on the upstream competition between the manufacturers is critical in understanding which firms gain and which firms lose. The upstream competition is affected in fundamentally different ways by quality information and fit information, and each information type has different implications for the retailer and manufacturers. Quality information homogenizes consumers' perceived utility differences between the two products and increases the upstream competition, which benefits the retailer but hurts the manufacturers. Fit information heterogenizes consumers' estimated fits to the products and softens the upstream competition, which hurts the retailer but benefits the manufacturers. Furthermore, reviews may also alter the nature of upstream competition from one in which consumers' own assessment on the quality dimension plays a dominant role in consumers' comparative evaluation of products to one in which fit dimension plays a dominant role. If manufacturers do not respond strategically to reviews and keep the same wholesale prices regardless of reviews (i.e., the upstream competition is assumed to be unaffected by reviews), then, we show that reviews never hurt the retailer and the manufacturer with favorable reviews, and never benefit the manufacturer with unfavorable reviews, a finding that demonstrates why reviews' effect on upstream competition is critical for firms in online marketplaces.

h i g h l i g h t sRecent progress in enhancing solar-to-hydrogen (STH) efficiency is reviewed. Light absorption, charge separation-migration and surface reaction are evaluated. Doping, quantum dot, and plasmon enhancement are the keys to high STH efficiency. Co-catalysts and nanostructured surfaces improve surface reactions effectively. Multiple excitons, upconversion, and synergic strategies are promising areas. a b s t r a c tSolar water splitting is a promising and ideal route for renewable production of hydrogen by using the most abundant resources of solar light and water. Focusing on the working principal of solar water splitting, including photon absorption and exciton generation in semiconductor, exciton separation and transfer to the surface of semiconductor, and respective electron and hole reactions with absorbed surface species to generate hydrogen and oxygen, this review covers the comprehensive efforts and findings made in recent years on the improvement for the solar-to-hydrogen efficiency (STH) determined by a combination of light absorption process, charge separation and migration, and catalytic reduction and oxidation reactions. Critical evaluation is attempted on the strategies for improving solar light harvesting efficiency, enhancing charge separation and migration, and improving surface reactions. Towards the end, new and emerging technologies for boosting the STH efficiency are discussed on multiple exciton generation, up-conversion, multi-strategy modifications and the potentials of organometal hybrid perovskite materials.

S-RNase is the female determinant of self-incompatibility (SI) in pear (). After translocation to the pollen tube, S-RNase degrades rRNA and induces pollen tube death in an -haplotype-specific manner. In this study, we found that the actin cytoskeleton is a target of S-RNase (PbrS-RNase) and uncovered a mechanism that involves phosphatidic acid (PA) and protects the pollen tube from PbrS-RNase cytotoxicity. PbrS-RNase interacts directly with PbrActin1 in an -haplotype-independent manner, causing the actin cytoskeleton to depolymerize and promoting programmed cell death in the self-incompatible pollen tube. Pro-156 of PbrS-RNase is essential for the PbrS-RNase-PbrActin1 interaction, and the actin cytoskeleton-depolymerizing function of PbrS-RNase does not require its RNase activity. PbrS-RNase cytotoxicity enhances the expression of phospholipase D (PbrPLDδ1), resulting in increased PA levels in the incompatible pollen tube. PbrPLDδ1-derived PA initially prevents depolymerization of the actin cytoskeleton elicited by PbrS-RNase and delays the SI signaling that leads to pollen tube death. This work provides insights into the orchestration of the S-RNase-based SI response, in which increased PA levels initially play a protective role in incompatible pollen, until sustained PbrS-RNase activity reaches the point of no return and pollen tube growth ceases.

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Rhenium-cyclized CCMSH analogues are novel melanoma-targeting metallopeptides with high tumor uptake, long tumor retention, and low background in normal tissues, which make these metallopeptides an ideal structural motif for designing novel melanoma-targeting agents. ReCCMSH has been derivatized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate so that it can be labeled with a wide variety of radionuclides for imaging and therapeutic applications. This study involved optimization of the in vivo biological properties of DOTA-ReCCMSH (S), through modification of the structure of the metallopeptide. Several DOTA-ReCCMSH analogues, Ac-Lys(DOTA)-ReCCMSH (4) DOTA-ReCCMSH(Arg(11)) (6), DOTA-ReCCMSH-OH (8), and DOTA-ReCCMSH-Asp-OH (10), were synthesized using solid phase peptide synthesis followed by rhenium cyclization. The IC(50) values of the metallopeptides were determined through competitive binding assays against (125)I-(Tyr(2))-NDP. Radiolabeling of the DOTA-rhenium-cyclized peptides with (111)In was carried out in NH(4)OAc (0.1 M; pH 5.5)-buffered solution for 30 min at 70 degrees C. The stability of the radiolabeled complexes was evaluated in 0.01 M, pH 7.4, phosphate-buffered saline/0.1% bovine serum albumin solution. After separation of the radiolabeled peptide from the unlabeled peptide by reverse phase high-performance liquid chromatography, the biodistribution of the radiolabeled complex was performed in C57 mice bearing B16/F1 murine melanoma tumors. All radiolabeled complexes showed fast blood clearance (2 h postinjection (pi): (111)In-S, 0.07 +/- 0.03% ID/g; (111)In-4, 0.09 +/- 0.06% ID/g; (111)In-6, 0.21 +/- 0.08% ID/g; (111)In-8, 0.11 +/- 0.10% ID/g; and (111)In-10, 0.05 +/- 0.03% ID/g), and their clearance was predominantly through the urine (4 h pi: 93.5 +/- 1.7, 87.8 +/- 6.5, 89.8 +/- 4.2, 93.3 +/- 1.1, and 93.8 +/- 1.8 (% ID) for (111)In-labeled S, 4, 6, 8, and 10, respectively). Tumor uptake values of 9.45 +/- 0.90, 6.01 +/- 2.36, 17.41 +/- 5.61, 9.27 +/- 0.68, and 7.32 +/- 2.09 (% ID/g) for (111)In-labeled S, 4, 6, 8, and 10, respectively, were observed at 4 h pi. The kidney uptake was 9.27 +/- 2.65% ID/g for (111)In-S, 19.02 +/- 2.63% ID/g for (111)In-4, 7.37 +/- 1.13% ID/g for (111)In-6, 8.70 +/- 0.88% ID/g for (111)In-8, and 8.13 +/- 1.47% ID/g for (111)In-10 at 4 h pi. Complex 6 showed high melanoma uptake and lower kidney uptake than the corresponding Lys(11) analogues, supporting 6 for further investigations as a potential therapeutic radiopharmaceutical.

Radiohalogenated ␣-melanocyte-stimulating hormone (␣-MSH) analogs were proposed for melanoma imaging and potential radiotherapy because ␣-MSH receptors are overexpressed on both mouse and human melanoma cell lines. However, biodistribution studies in tumor-bearing mice with radiohalogenated ␣-MSH peptides showed very rapid tumor radioactivity wash out due to lysosomal degradation of the radiohalogenated complex after internalization, which decreased the therapeutic efficacy significantly (