A New SiF–Dipropargyl Glycerol Scaffold as a Versatile Prosthetic Group to Design Dimeric Radioligands: Synthesis of the [ 18 F]BMPPSiF Tracer to Image Serotonin Receptors

A novel SiX–dipropargyl glycerol scaffold (X: H, F, or 18 F) was developed as a versatile prosthetic group that provides technical advantages for the preparation of dimeric radioligands based on silicon fluoride acceptor pre‐ or post‐labeling with fluorine‐18. Rapid conjugation with the prosthetic group takes place in microwave‐assisted click conjugation under mild conditions. Thus, a bivalent homodimeric SiX–dipropargyl glycerol derivatized radioligand, [ 18 F]BMPPSiF, with enhanced affinity was developed by using click conjugation. High uptake of the radioligand was demonstrated in 5‐HT 1A receptor‐rich regions in the brain with positron emission tomography. Molecular docking studies (rigid protein–flexible ligand) of BMPPSiF and known antagonists (WAY‐100635, MPPF, and MefWAY) with monomeric, dimeric, and multimeric 5‐HT 1A receptor models were performed, with the highest G score obtained for docked BMPPSiF: −6.766 as compared with all three antagonists on the monomeric model. Multimeric induced‐fit docking was also performed to visualize the comparable mode of binding under in vivo conditions, and a notably improved G score of −8.455 was observed for BMPPSiF. These data directly correlate the high binding potential of BMPPSiF with the bivalent binding mode obtained in the biological studies. The present study warrants wide application of the SiX–dipropargyl glycerol prosthetic group in the development of ligands for imaging with enhanced affinity markers for specific targeting based on peptides, nucleosides, and lipids.

A randomized, open‐label clinical trial of tasisulam sodium versus paclitaxel as second‐line treatment in patients with metastatic melanoma

BACKGROUND Tasisulam sodium (hereafter referred to as tasisulam) is a novel, highly albumin‐bound agent that demonstrated activity in a phase 2 melanoma study. METHODS In this open‐label phase 3 study, patients with AJCC stage IV melanoma received tasisulam (targeting an albumin‐corrected exposure of 1200‐6400 h (hour).μg/mL on day 1) or paclitaxel (80 mg/m 2 on days 1, 8, and 15) every 28 days as second‐line treatment. RESULTS The study was placed on clinical hold after randomization of 336 patients when a safety review indicated an imbalance of possibly drug‐related deaths in the tasisulam arm. Efficacy results for tasisulam versus paclitaxel revealed a response rate of 3.0% versus 4.8%, a median progression‐free survival of 1.94 months versus 2.14 months ( P  = .048), and a median overall survival of 6.77 months versus 9.36 months ( P  = .121). The most common drug‐related grade ≥3 laboratory toxicities (graded according to Common Terminology for Adverse Events [version 3.0]) were thrombocytopenia (18.9%) for patients treated with tasisulam and neutropenia/leukopenia (8.7%) among those receiving paclitaxel. There were 13 possibly related deaths reported to occur on the study, with the majority occurring during cycle 2 in the setting of grade 4 myelosuppression, all in the tasisulam arm. Investigation of the unexpectedly high rate of hematologic toxicity revealed a subset of patients with low tasisulam clearance, leading to drug accumulation and high albumin‐corrected exposure in cycle 2. CONCLUSIONS Although the study was stopped early because of safety issues in the tasisulam arm, tasisulam was considered unlikely to be superior to paclitaxel, and paclitaxel activity in the second‐line treatment of melanoma was much lower than expected. The toxicity imbalance was attributed to an unexpectedly low tasisulam clearance in a subset of patients, underscoring the importance of pharmacokinetic monitoring of compounds with complex dosing, even in late‐phase studies. Cancer 2014;120:2016–2024 . © 2014 American Cancer Society .

Everolimus in combination with octreotide long‐acting repeatable in a first‐line setting for patients with neuroendocrine tumors: An ITMO group study

BACKGROUND Preclinical and clinical studies suggest synergistic activity between somatostatin analogues and mammalian target of rapamycin inhibitors. The activity and safety of everolimus was assessed in combination with octreotide long‐acting repeatable (LAR) in patients with neuroendocrine tumors (NETs) of gastroenteropancreatic and lung origin. METHODS This was a phase 2, multicenter trial using a Simon's 2‐stage minimax design. Treatment‐naive patients with advanced well‐differentiated NETs of gastroenteropancreatic tract and lung origin received everolimus 10 mg daily, in combination with octreotide LAR 30 mg every 28 days. The primary endpoint was objective response rate (ORR). RESULTS A total of 50 patients (median age, 60.5 years) were enrolled. Primary tumor sites were: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum and duodenum (2 patients), and unknown (14 patients). Thirteen patients (26%) had carcinoid syndrome. Treatment‐related adverse events (AEs) were mostly grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, whereas grade 3 AEs included skin rash in 1 case (2%), stomatitis in 4 cases (8%), and diarrhea in 11 cases (22%). The ORR was 18%; 2% of patients had a complete response (CR), 16% a partial response (PR) and 74% achieved stable disease (SD). All CRs and all PRs as well as 92% of SDs had a duration ≥6 months. The clinical benefit (CR+PR+SD) was 92%. At a median follow‐up of 277 days, median time to progression and overall survival were not reached. CONCLUSIONS The everolimus‐octreotide LAR combination was active and well tolerated in these previously treated patients with advanced NETs, suggesting a possible role as first‐line treatment in patients with NET. Cancer 2014;120:2457–2463. © 2014 American Cancer Society .

The value of the “suspicious for urothelial carcinoma” cytology category: A correlative study of 4 years including 337 patients

BACKGROUND The terminology used in reporting urine cytology lacks uniformity and the significance of the “atypical” and “suspicious” categories is still not well established. This results in variable clinical follow‐up and management of those cases. The authors sought to investigate the prognostic value of a diagnosis of “suspicious for high‐grade urothelial carcinoma” (HGUCA). METHODS All cases with a “suspicious” or “positive” cytological diagnosis spanning 4 years were included and correlated with the subsequent biopsies obtained within 6 months of urine collection. RESULTS A total of 447 correlative events (57% positive and 43% suspicious) corresponding to 773 cytology specimens and 337 patients were included. The morphology of the “suspicious” cells was similar to what has recently been reported in the literature as “atypical urothelial cells, cannot exclude HGUCA.” A “suspicious” diagnosis was more often rendered than a “positive” one in voided specimens (80% vs 65%, respectively). The mean interval between cytology and biopsy was 31 days. On follow‐up, 92% of “suspicious” diagnoses (176 of 191 diagnoses) and 90% of “positive” diagnoses (230 of 256 diagnoses) were found to have a biopsy with a diagnosis of carcinoma (low grade or high grade). A diagnosis of HGUCA followed a “suspicious” and a “positive” diagnosis in 79% and 86% of cases, respectively. CONCLUSIONS A “suspicious” diagnosis as defined in the current study warrants close investigations and repeat biopsy to rule out HGUCA. In addition, the findings of the current study raise the question of the need for quantitative criteria for diagnosing HGUCA on cytology. Cancer (Cancer Cytopathol) 2014;122:796–803 . © 2014 American Cancer Society .

Issue information

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Issue information

Chromaticity‐matched but spectrally different light source effects on simple and complex color judgments

As light‐emitting diode (LED) light sources mature, lighting designers will be able to deliver white light with a variety of spectral power distributions and a variety of color rendering properties. This experiment examined the effects of three spectral power distributions (SPDs) that were matched in illuminance and chromaticity on three measures of color perception: one objective (performance on the Farnsworth‐Munsell 100 hue test) and two subjective (judgments of the attractiveness of one's own skin, and preferences for the saturation of printed images). The three SPDs were a quartz‐halogen (QH) lamp and two LED sources that were matched to the QH lamp in terms of both illuminance and chromaticity; the three light sources were nominally CCT = 3500 K, x  = 0.40, y  = 0.39 and ∼ 400 lx. LED A used three channels (red, green, blue), and had very poor color rendering ( R a  = 18). LED B used four channels (red, amber, cyan, white) and had very good color rendering ( R a  = 96, whereas the QH had R a  = 98). Secondary hypotheses addressed the effects of age and skin and eye color on the dependent measures. As expected, LED A delivered very different color perceptions on all measures when compared to QH; LED B did not differ from QH. The results show that it is possible for LED sources to match the familiar incandescent sources. However, although it is possible to deliver what appear to be millions of colors with a three‐chip (RGB) device, there is the risk of creating a very poor luminous environment. © 2013 National Research Council Canada and Wiley Periodicals, Inc. Col Res Appl, 39, 263–274, 2014; Published Online 12 April 2013 in Wiley Online Library ( wileyonlinelibrary.com ). DOI 10.1002/col.21811

Combining geo‐referencing and network coding for distributed large‐scale information management

Summary The widespread and ubiquitous availability of Internet access enables the collective sharing of huge amount of data generated by heterogeneous sources. For example, the information, which will be exchanged among entities (sensors, people, and services) of future smart cities to enhance the security and lifestyle of their citizens, poses the challenging question of how this information can be efficiently and effectively maintained across the city. In this article, we propose a decentralized approach, based on the distributed geographic table (DGT) overlay scheme, which exploits geo‐referenced information about nodes to achieve efficient data management. After recalling DGT main concepts, we illustrate the possible node types and how information can be published and retrieved within the network. To cope with the unavoidable node failures and disconnections, our approach leverages upon randomized network coding to increase the robustness of publish/retrieval operations. Evaluation is carried out through an extensive simulation analysis for a realistic urban scenario using the metrics of efficiency in data publication/search, resource availability, and storage occupancy requirements. Results show the approach effectiveness for large‐scale sharing of geo‐referenced information and tradeoffs between redundancy overhead and resource availability. A few results obtained with a preliminary DGT implementation are also presented in the paper. Copyright © 2014 John Wiley & Sons, Ltd.

Photocatalytic Carboxylation of Organic Substrates with Carbon Dioxide at Zinc Sulfide with Deposited Ruthenium Nanoparticles

Photocatalytic carboxylation of acetylacetone with carbon dioxide has been performed by using ZnS‐based photocatalysts. The formation of two isomeric carboxylic acids, as proven by IR and 13 C NMR spectroscopy, was observed. The reaction yield was enhanced after deposition of ruthenium nanoparticles on ZnS. The reaction encompasses ruthenium‐mediated one‐electron reduction of CO 2 to CO 2 .− with electrons from the conduction band of ZnS and one‐hole oxidation of acetylacetone to the relevant radical. Coupling of photogenerated radicals leads to the formation of carboxylic acids. Generation of CO 2 .− has been confirmed by spin‐trapping EPR measurements. The process described herein may find applications for the solar‐light‐driven green synthesis of C n +1 carboxylic compounds from C n substrates by utilising carbon dioxide.