bluuebunny/crossref_metadata_2025 huggingface dataset:
Eco‐Friendly Combination of the Immobilized PGA Enzyme and the S‐Phacm Protecting Group for the Synthesis of Cys‐Containing Peptides
Authors: Góngora‐Benítez Miriam , Basso Alessandra , Bruckdorfer Thomas , Royo Miriam , Tulla‐Puche Judit , Albericio Fernando
Published: October 2012

Enzyme‐labile protecting groups have emerged as a green alternative to conventional protecting groups. These groups introduce a further orthogonal dimension and eco‐friendliness into protection schemes for the synthesis of complex polyfunctional organic molecules. S‐Phacm, a Cys‐protecting group, can be easily removed by the action of a covalently immobilized PGA enzyme under very mild conditions. Herein, the versatility and reliability of an eco‐friendly combination of the immobilized PGA enzyme and the S‐Phacm protecting group has been evaluated for the synthesis of diverse Cys‐containing peptides.
Cyclohexyne Cycloinsertion in the Divergent Synthesis of Guanacastepenes
Authors: Gampe Christian M. , Carreira Erick M.
Published: October 2012

The guanacastepenes are a family of 15 diterpenes that share a common 5‐6‐7 tricyclic core, which is decorated with quaternary centers, unsaturation, hydroxyl and carbonyl groups. Some of these natural products show interesting antimicrobial potency. Their collective structural and biological features have stirred up vibrant activity among organic chemists. Herein, we disclose an account of our studies toward the synthesis of a number of guanacastepenes. The synthetic strategy relies on the use of cyclohexyne in a cycloinsertion reaction to rapidly construct the guanacastepene core. Isolation of a cyclobutenol as intermediate in the cyclohexyne cycloinsertion provided us with the possibility to study further the reactivity of this metastable compound, and we uncovered novel rearrangements and ring‐opening reactions. Stereoselective, late‐stage oxidative diversification of the carbon scaffold allowed the synthesis of guanacastepenes N and O and paved the way for the synthesis of guanacastepenes H and D.
ChemInform Abstract: Na3B3O3F6: Synthesis, Crystal Structure, and Ionic Conductivity.
Authors: Cakmak Gueliz , Pilz Thomas , Jansen Martin
Published: October 2012

The title compound is synthesized either by reaction of NaBF4 and H3BO3 in the presence of hexane (Pt crucible; 1.
ChemInform Abstract: Hydrolysis Studies on Bismuth Nitrate: Synthesis and Crystallization of Four Novel Polynuclear Basic Bismuth Nitrates.
Authors: Miersch L. , Rueffer T. , Schlesinger M. , Lang H. , Mehring M.
Published: October 2012

The structures of (II)—(V) are determined by single crystal XRD.
ChemInform Abstract: Synthesis, Structure, and Characterization of New Li+—d0—Lone‐Pair — Oxides: Noncentrosymmetric Polar Li6(Mo2O5)3 (SeO3)6 and Centrosymmetric Li2(MO3)(TeO3) (M: Mo6+ or W6+).
Authors: Nguyen Sau Doan , Halasyamani P. Shiv
Published: October 2012

Compounds (III) and (VII) are characterized by single crystal XRD, IR and UV/VIS diffuse reflectance spectroscopy, second harmonic generation, piezoelectric, and polarization measurements, and electron localization function computations using the plane‐wave pseudopotential method.
ChemInform Abstract: Convenient Method for Reduction of C—N Double Bonds in Oximes, Imines, and Hydrazones Using Sodium Borohydride—Raney Ni System.
Authors: Yang Yihua , Liu Shouxin , Li Junzhang , Tian Xia , Zhen Xiaoli , Han Jianrong
Published: October 2012

An efficient method for the reduction of C—N double bonds is successfully applied to a wide range of oximes, imines and hydrazones.
ChemInform Abstract: Chlorination of Aliphatic Primary Alcohols via Triphosgene—Triethylamine Activation.
Authors: Ayala Caitlan E. , Villalpando Andres , Nguyen Alex L. , McCandless Gregory T. , Kartika Rendy
Published: October 2012

Diols bearing a primary and a tertiary hydroxyl group such as (Ia) and (Ib) are selectively chlorinated at the primary function.
ChemInform Abstract: Ni(0)/NHC‐Catalyzed Amination of N‐Heteroaryl Methyl Ethers Through the Cleavage of Carbon—Oxygen Bonds.
Authors: Tobisu Mamoru , Yasutome Ayaka , Yamakawa Ken , Shimasaki Toshiaki , Chatani Naoto
Published: October 2012

Optimized conditions are developed for the conversion of electron‐deficient substrates to the corresponding amino‐substituted derivatives.
ChemInform Abstract: Oxidative Imination of Toluenes Catalyzed by Pd—Au/Silica Gel under Mild Reaction Conditions.
Authors: Cui Xinjiang , Shi Feng , Deng Youquan
Published: October 2012

A heterogenous bimetallic catalyst is prepared and successfully applied for the oxidative imination of toluenes with amines (I) and sulfonamides (IV).
ChemInform Abstract: Polystyrene‐Supported Pyridinium Chloroaluminate Ionic Liquid as a New Heterogeneous Lewis Acid Catalyst for Knoevenagel Condensation.
Authors: Boroujeni Kaveh Parvanak , Jafarinasab Mina
Published: October 2012

The catalyst is synthesized from commercially available Merrifield resin, pyridine and AlCl3 and successfully applied in the Knoevenagel condensation of aromatic and aliphatic aldehydes with ethyl cyanoacetate (I) as well as in the Michael reaction of hydroxycoumarin (X) with benzaldehyde.
ChemInform Abstract: Highly Efficient Solvent‐Free Acetylation of Alcohols with Acetic Anhydride Catalyzed by Recyclable Sulfonic Acid Catalyst (SBA‐15‐Ph—Pr—SO3H) — An Environmentally Benign Method.
Authors: Zareyee Daryoush , Ghadikolaee Abdollah Razaghi , Khalilzadeh Mohammad A.
Published: October 2012

A highly thermal stable, hydrophobic, reusable (5 times), easily preparable, and complete heterogeneous catalyst, which can also be stored and handled under open air , is successfully applied to the title reaction.
ChemInform Abstract: Synthesis of gem‐Dihaloenynes and Butatrienes from gem‐Dihalovinyl Derivatives.
Authors: Meng Tianhao , Zhang Hui‐Jun , Xi Zhenfeng
Published: October 2012

A BuLi‐mediated Fritsch—Buttenberg—Wiechell rearrangement of tetrahalobutadienes gives the gem‐dihaloenyne products in good yields.
ChemInform Abstract: An Efficient Synthesis of Tertiary Amines from Nitriles in Aprotic Solvents.
Authors: Shares Jonathan , Yehl Jenna , Kowalsick Amanda , Byers Philip , Haaf Michael P.
Published: October 2012

The process affords the desired amines, required as non‐nucleophilic proton scavengers, exclusively from nitriles (I) in THF, hexanes or pentane.
ChemInform Abstract: A Robust, Efficient, and Highly Enantioselective Method for Synthesis of Homopropargyl Amines.
Authors: Vieira Erika M. , Haeffner Fredrik , Snapper Marc L. , Hoveyda Amir H.
Published: October 2012

The first general, practical, scalable, and efficient method for the synthesis of the title compounds is developed by using an inexpensive metal salt and a readily preparable ligand (five steps).
ChemInform Abstract: N,N‐Dichlorotriflamide in the Reaction with Cinnamic Acid.
Authors: Kondrashov E. V. , Popov A. V. , Chernyshev K. A. , Serykh V. Yu. , Rozentsveig I. B.
Published: October 2012

An uncommon chloroamidation of cinnamic acid accompanied by a decarboxylation is observed on reacting cinnamic acid with triflamide (II) in water in the absence of any catalyst.
ChemInform Abstract: Efficient Microwave‐Assisted Pd‐Catalyzed Hydroxylation of Aryl Chlorides in the Presence of Carbonate.
Authors: Yu Chao‐Wu , Chen Grace S. , Huang Chen‐Wei , Chern Ji‐Wang
Published: October 2012

Using a weak base carbonate, even the hydroxylation of chlorides bearing an ester (IIe) or a free amide (IIf) group succeeds without hydrolysis.
ChemInform Abstract: Combination of NH2OH·HCl and NaIO4: A New and Mild Oxidizing Agent for Selective Oxidation of Alcohols to Carbonyl Compounds.
Authors: Majee Adinath , Kundu Shrishnu Kumar , Santra Sougata , Hajra Alakananda
Published: October 2012

The optimized process is advantageous with regard to simple operation, fast reaction, and neutral conditions.
ChemInform Abstract: Oxofunctionalized trans‐2‐Carboxycinnamic Acids by Catalytic Domino Oxidation of Naphthols and Hydronaphthoquinones.
Authors: Giurg Miroslaw , Muchalski Hubert , Kowal Ewa
Published: October 2012

Both β‐ (I) and α‐naphthols (III) are converted to carboxycinnamic acids (II) by hydrogen peroxide oxidation in the presence of a diaryl diselenide.
ChemInform Abstract: Nitromethyl Benzoate Annulation Reactions: A Rapid Construction of the Stealthin Skeleton.
Authors: Kraus George A. , Chaudhary Divya , Yuan Yi , Schuster Andrew
Published: October 2012

A Michael addition/Claisen condensation sequence affords polycyclic adducts representing the carbocyclic framework of stealthins.
ChemInform Abstract: Synthesis and Characterization of Novel Ionic Liquids: N‐Substituted Aziridinium Salts.
Authors: Duriska Martin B. , Grondin Joseph , Servant Laurent , Birot Marc , Deleuze Herve
Published: October 2012

Some representative compounds of a new family of room‐temperature ionic liquids built from aziridinium cations are prepared.
ChemInform Abstract: Efficient Palladium‐Catalyzed Synthesis of Substituted Indoles Employing a New (Silanyloxyphenyl)phosphine Ligand.
Authors: Lavery Christopher B. , McDonald Robert , Stradiotto Mark
Published: October 2012

The APT ligand is prepared in 2 steps from o‐bromophenol.
ChemInform Abstract: Synthesis of Certain 2‐Substituted‐1H‐benzimidazole Derivatives as Antimicrobial and Cytotoxic Agents.
Authors: Taher Azza Taher , Khalil Nadia Abdalla , Ahmed Eman Mohamed , Ragab Yasser Mohamed
Published: October 2012

All new benzimidazole derivatives show potent antimicrobial activities against some species of Gram‐negative bacteria (P.
ChemInform Abstract: Substituted [1,3,4]‐Oxadiazole, [1,3,4]‐Thiadiazole and [1,2,4]‐Triazole; Synthesis, Characterization and Antimicrobial Study.
Authors: Deohate Pradip P.
Published: October 2012

A variety of benzotriazolylmethyl‐substituted oxadiazole, thiadiazole and triazole derivatives are synthesized via oxidative cyclization reactions of acetamidothiourea derivatives (III).
ChemInform Abstract: In vitro Antifungal Activity of Some New Triazole Compounds.
Authors: Chanda Sumitra , Baluja Shipra , Parekh Jigna
Published: October 2012

Some of the triazole derivatives obtained (IV) (10 examples) show significant antifungal activity similar or even better than the standard drugs.
ChemInform Abstract: “Click” Synthesis of a Triazole‐Based Inhibitor of Met Functions in Cancer Cells.
Authors: Passarella Daniele , et al. et al.
Published: October 2012

Compound (I) inhibits the HGF‐induced scattering of MDCK (epithelial cells) and in vitro tumorigenesis of H1437 (non‐small‐cell lung cancer) and GTL‐16 (human gastric carcinoma).
ChemInform Abstract: Phosphomolybdic Acid (H3Mo12O40P) as a Reusable Heterogeneous Catalyst for the Synthesis of 5‐Substituted 1H‐Tetrazoles via [2 + 3] Cycloaddition of Nitriles and Sodium Azide.
Authors: Takale Santosh , Manave Smita , Phatangare Kiran , Padalkar Vikas , Darvatkar Nitin , Chaskar Atul
Published: October 2012

The applied catalyst can be reused several times.
ChemInform Abstract: Asymmetric Friedel—Crafts Alkylation of Indoles with 3‐Nitro‐2H‐chromenes Catalyzed by Diphenylamine‐Linked Bis(oxazoline) and Bis(thiazoline) Zn(II) Complexes.
Authors: Jia Yang , Yang Wen , Du Da‐Ming
Published: October 2012

The mild and efficient title reaction leads to medicinally privileged indolyl(nitro)chromans.
ChemInform Abstract: An Efficient Intermolecular [Pd]‐Catalyzed C—C and Intramolecular [Cu]‐Catalyzed C—O Bonds Formation: Synthesis of Functionalized Flavans and Benzoxepine.
Authors: Suchand B. , Krishna J. , Ramulu B. Venkat , Dibyendu D. , Reddy A. Gopi Krishna , Mahendar L. , Satyanarayana G.
Published: October 2012

A three step synthesis of flavans is based on the copper catalyzed cyclization of propanol derivatives (V) and (VII).
ChemInform Abstract: Potassium Phosphate Catalyzed Efficient Synthesis of 3‐Carboxycoumarins.
Authors: Undale Kedar A. , Gaikwad Dipak S. , Shaikh Tarannum S. , Desai Uday V. , Pore Dattaprasad M.
Published: October 2012

An efficient and fast synthesis of the title compounds (III) (11 examples) is achieved by reaction of salicylaldehyde (I) with Meldrum′s acid using potassium phosphate as an inexpensive catalyst.
ChemInform Abstract: Enantioselective Friedel—Crafts Alkylation of Indoles with 2‐Enoylpyridine‐N‐oxides Catalyzed by glucoBOX‐Cu(II) Complex.
Authors: George Jimil , Reddy B. V. Subba
Published: October 2012

The use of sugar‐based chiral ligands renders possible a highly efficient reaction in a short reaction time.
ChemInform Abstract: An Efficient Synthesis of 2‐Alkylpyridines Using an Alkylation/Double Decarboxylation Strategy.
Authors: Donald Craig , Boyd Scott
Published: October 2012

A convenient method is presented for the synthesis of 2‐alkylpyridines from pyridyl malonate ester (I) via alkylation with alkyl bromides and subsequent hydrolysis and double decarboxylation.
ChemInform Abstract: Synthesis of Novel 6‐Substituted Sulfur‐Containing Derivatives of Pyridoxine.
Authors: Shtyrlin Nikita V. , Pavelyev Roman S. , Pugachev Mikhail V. , Sysoeva Lubov P. , Musin Rashid Z. , Shtyrlin Yurii G.
Published: October 2012

Derivatives bearing 1,2 or 3 chloro substituents are prepared and used as starting materials for different types of title compounds.
ChemInform Abstract: Chiral Counteranion‐Directed Silver‐Catalyzed Asymmetric Synthesis of 1,2‐Dihydroisoquinolines by Friedel—Crafts Alkylation Reactions.
Authors: Zhang Jun‐Wei , Xu Zhe , Gu Qing , Shi Xiao‐Xin , Leng Xue‐Bing , You Shu‐Li
Published: October 2012

Best results are obtained with the binol‐derived silver phosphate BSP in the reaction of o‐alkynyl‐substituted aldimines with indoles.
ChemInform Abstract: Discovery, Oral Pharmacokinetics and in vivo Efficacy of a Highly Selective 5‐HT4 Receptor Agonist: Clinical Compound TD‐2749.
Authors: Long Daniel D. , et al. et al.
Published: October 2012

Application of the previously reported multivalent approach to drug discovery towards 5‐HT4 receptor agonists results in the identification of (I), which is selected as a development candidate.
ChemInform Abstract: Hydrothiolation and Intramolecular Cyclization Sequence for the Synthesis of 1,3‐Oxathiine Frameworks.
Authors: Nishina Yuta , Miyata Junya
Published: October 2012

Starting from thiosalicylic acid, unactivated alkynes in the presence of a Pd‐catalyst and activated alkynes in the absence of the catalyst are selectively transformed to the desired heterocycles without any by‐products.
ChemInform Abstract: “On Water” Direct Pd‐Catalyzed C—H Arylation of Thiazolo[5,4‐d]pyrimidine Derivatives.
Authors: Su Ye‐Xiang , Deng Ya‐Hui , Ma Ting‐Ting , Li Yu‐Yan , Sun Li‐Ping
Published: October 2012

The reaction requires 2 equiv.
ChemInform Abstract: 1,3‐Oxazinan‐2‐ones from Amines and 1,3‐Diols Through Dialkyl Carbonate Chemistry.
Authors: McElroy Con Robert , Arico Fabio , Tundo Pietro
Published: October 2012

The one‐pot base‐mediated cascade reaction is tested with 4 diesters and the mixed derivative (VI) bearing a sterically hindered ‐tBu group is found to be the most efficient one.
ChemInform Abstract: Oxidative Metal‐Free Cross‐Coupling of Secondary Phosphine Chalcogenides and Benzenediols: Synthesis of Phosphinochalcogenoic O‐Diesters.
Authors: Gusarova Nina K. , Volkov Pavel A. , Ivanova Nina I. , Larina Ludmila I. , Trofimov Boris A.
Published: October 2012

Hitherto unknown phosphinochalcogenoic O‐diesters (III) are obtained under mild conditions.
ChemInform Abstract: The New Cassane‐Type Diterpenes from Caesalpinia minax.
Authors: Ma Guo‐Xu , Yuan Jing‐Quan , Cao Li , Yang Jun‐Shan , Xu Xu‐Dong
Published: October 2012

Neocaesalpin S (Ia), T (Ib), U (Ic) and V (II) show mild antiproliferative activities against liver cancer (HepG‐2) and breast cancer (MCF‐7).
ChemInform Abstract: Recognition of myo‐Inositol 1,4,5‐Trisphosphate Using a Fluorescent Imidazolium Receptor.
Authors: Jung Ji Young , Jun Eun Jin , Kwon Yong‐Uk , Yoon Juyoung
Published: October 2012

Derivative (I) shows a selective fluorescent change with D‐myo‐IP3 among the various IP series, pyrophosphate, and ATP.
ChemInform Abstract: Intrinsic Lifetimes and Kinetic Stability in Media of Noble‐Gas Hydrides
Authors: Gerber R. Benny , Tsivion Ehud , Khriachtchev Leonid , Raesaenen Markku
Published: October 2012

Review: 63 refs.
ChemInform Abstract: The Chemistry of Arsenic, Antimony and Bismuth
Authors: Burford Neil , Carpenter Yuen‐ying , Conrad Eamonn , Saunders Cheryl D. L.
Published: October 2012

Review: 75 refs.
ChemInform Abstract: Introduction to the Organometallics in Biology and Medicine Issue
Authors: Coogan Michael P.
Published: October 2012

Review: 10 refs.
ChemInform Abstract: Dithioethers as Ligands in Coordination and Organometallic Chemistry: From Molecules to Materials
Authors: Knorr M. , Guyon F.
Published: October 2012

Review: 69 refs.
ChemInform Abstract: Recent Advances in Asymmetric Isocyanide‐Based Multicomponent Reactions
Authors: van Berkel Sander S. , Boegels Berry G. M. , Wijdeven Marloes A. , Westermann Bernhard , Rutjes Floris P. J. T.
Published: October 2012

Review: 117 refs.
ChemInform Abstract: Extended Pseudoasymmetry and Geometric Prochirality Clarifying the Scope of the Concepts of Holantimers and Stereoisograms
Authors: Fujita Shinsaku
Published: October 2012

Review: 56 refs.
ChemInform Abstract: Multicomponent Heterocyclization Reactions with Controlled Selectivity
Authors: Chebanov V. A. , Desenko S. M.
Published: October 2012

Review: 72 refs.
ChemInform Abstract: Group‐10 Metal Complexes of Biological Molecules and Related Ligands: Structural and Functional Properties
Authors: Shimazaki Yuichi , Yamauchi Osamu
Published: October 2012

Review: 73 refs.
ChemInform Abstract: Gas‐Phase Basicities of Polyfunctional Molecules. Part 2. Saturated Basic Sites
Authors: Bouchoux Guy , Salpin Jean‐Yves
Published: October 2012

Review: 172 refs.
ChemInform Abstract: Micro‐/Nanostructured Mechanical Metamaterials
Authors: Lee Jae‐Hwang , Singer Jonathan P. , Thomas Edwin L.
Published: October 2012

Review: 315 refs.
ChemInform Abstract: Towards High‐Performance Bioinspired Composites
Authors: Studart Andre R.
Published: October 2012

Review: 217 refs.
Using sampled information: is it enough for the sparse matrix–vector product locality optimization?
Authors: Pichel Juan C. , Lorenzo Juan A. , Rivera Francisco F. , Heras Dora B. , Pena Tomás F.
Published: October 2012

One of the main factors that affect the performance of the sparse matrix–vector product (SpMV) is the low data reuse caused by the irregular and indirect memory access patterns. Different strategies to deal with this problem such as data reordering techniques have been proposed. The computational cost of these techniques is typically high because they consider all the nonzeros of the sparse matrix in order to find an appropriate permutation of rows and columns that improves the SpMV performance. In this paper, we analyze the possibility of increasing the locality of the SpMV using incomplete information in the reordering process. This partial information comes as a consequence of considering only a subset of the nonzero elements of the matrix. These nonzeros are obtained from the original matrix through a sampling process. In particular, two different sampling methods have been considered: a random sampling and an event‐based sampling using hardware counters. We have detected that a small number of samples is enough to obtain quality reorderings. As a consequence, using sampling‐based reorderings leads to noticeable performance improvements with respect to the non‐reordered matrices, reaching speedup values up to 2.1 × . In addition, an important reduction in the computational time required by the reordering technique has been observed. Copyright © 2012 John Wiley & Sons, Ltd.
Design of a 1‐GSample/s 9‐b double sampling track‐and‐hold amplifier in BiCMOS technology
Authors: Lin Hung‐Yi , Lai Yen‐Tai
Published: October 2012

This paper gives a detail presentation of a fully pseudo‐differential open‐loop BiCMOS track‐and‐hold amplifier (THA) for 9‐b operation up to 1 GSample/s. The proposed THA not only uses a double sampling technique to increase the achievable sampling frequency by a factor of two, but also employs a linearization technique to reduce the gain dependence of the THA input stage upon the input level. Moreover, timing mismatch between the clock signals of the two interleaved paths is minimized by means of a timing mismatch insensitive clock generator controlled by a common master sampling clock. The post‐layout simulation results using TSMC 75 GHz fT, 0.35‐µm SiGe BiCMOS technology show that the proposed architecture achieve a signal to noise and distortion ratio of 53.92 dB, equivalent to the effective number of bits of 8.66‐b for 58.11 MHz input frequency at 1 GSample/s. The power dissipation of the whole THA is 161.1 mW. Copyright © 2012 John Wiley & Sons, Ltd.
Companion Diagnostics and the Drug–Diagnostic Codevelopment Model
Authors: Jørgensen Jan Trøst
Published: October 2012

Preclinical Research

The concept of using a predictive or selective diagnostic assay in relation to drug development goes back to the 1970s when the selective estrogen receptor modulator, tamoxifen (AstraZeneca) was developed for metastatic breast cancer. Clinical data showed that the estrogen receptor status correlated well with the clinical outcome when the patients were treated with tamoxifen. Although this datum was published more than 35 years ago, the adaption of the drug–diagnostic codevelopment model has been relatively slow, and it is only within the last decade that it has gained widespread acceptance. In this model, the drug and the diagnostic are interdependent, and if the development project proves successful, the companion diagnostic assay (CoDx) will end up determining the conditions for the use of the drug. This gatekeeper role obviously requires that the CoDx assays adhere to the same strict rules and regulations that are known from the development of drugs. For any CoDx assay, it must be documented that it is robust and reliable and that it possesses clinical utility. The article focus on some of the most important aspects of the CoDx development process with emphasis on the clinical validation and clinical utility but also other critical issues such as the biomarker selection process, determination of the cut‐off value, and the analytical validation are discussed.
Ensemble Classification of Cancer Types and Biomarker Identification
Authors: Hijazi Hussein , Wu Ming , Nath Aritro , Chan Christina
Published: October 2012

Preclinical Research

Cancer classification is an important step in biomarker identification. Developing machine learning methods that correctly predict cancer subtypes/types can help in identifying potential cancer biomarkers. In this commentary, we presented ensemble classification approach and compared its performance with single classification approaches. Additionally, the application of cancer classification in identifying biomarkers for drug design was discussed.
Berberine Modulates Epigenetics via Inhibition of Hypoxia‐Induced Histone Lysine Demethylases Expression
Authors: Vavilala Divya Teja , Vadlapatla Ramya Krishna , Ponnaluri VK Chaithanya , Prakash Swami , Mukherji Mridul
Published: October 2012

Preclinical Research

Pathological neovascularization during ischemic retinopathies is the major cause of blindness. The underlying cause of neovascularization is activation of the hypoxia‐inducible factor (HIF) pathway leading to expression of pro‐angiogenic factors. Recent studies have established that histone lysine demethylases (KDMs) play an important role in the HIF‐mediated expression of pro‐angiogenic factors under hypoxic conditions. Thus, inhibitors of the HIF pathway can be used for the treatment of these debilitating diseases. Here, we show that berberine, a plant alkaloid with a long history of medicinal use, is a potent inhibitor of the HIF pathway and hypoxia‐induced expression of KDMs in a number of retinal pigment epithelial and cancer cell lines. Treating these cells with berberine leads to inhibition of KDMs‐mediated induction of pro‐angiogenic genes (adrenomedullin and growth differentiation factor 15) under hypoxic conditions. Because berberine has been used in eyedrops to treat trachoma, our results suggest that its proper delivery to the back of the eye may treat retinal and choroidal neovascularization during ischemic retinopathies.
Analysis of 30 synthetic cannabinoids in oral fluid using liquid chromatography‐electrospray ionization tandem mass spectrometry
Authors: Kneisel Stefan , Auwärter Volker , Kempf Jürgen
Published: October 2012

In recent years, the analysis of synthetic cannabinoids in human specimens has gained enormous importance in the broad field of drug testing. Nevertheless, the considerable structural diversity among synthetic cannabinoids already identified in ‘herbal mixtures’ hampers the development of comprehensive analytical methods. As the identification of the main metabolites of newly appearing substances is very laborious and time‐consuming, the detection of the parent compounds in blood samples is the current approach of choice for drug abstinence testing. Whenever blood sampling is not possible however, the need for alternative matrices arises.

In this article, we present a fully validated liquid chromatography‐electrospray ionization tandem mass spectrometry (LC/ESI‐MS/MS) method for the analysis of 30 synthetic cannabinoids in oral fluid samples collected with the Dräger DCD 5000 collection device. The method proved to be suitable for the quantification of 28 substances. The limits of detection were in the range from 0.015 to 0.9 ng/ml, while the lower limits of quantification ranged from 0.15 to 3.0 ng/ml. The method was successfully applied to 264 authentic samples during routine analysis. A total of 31 samples (12%) was tested positive for at least one of the following synthetic cannabinoids: AM‐694, AM‐2201, JWH‐018, JWH‐019, JWH‐081, JWH‐122, JWH‐203, JWH‐210, JWH‐250, JWH‐307, MAM‐2201, and RCS‐4. Given that stabilization of the collection pads after sampling is warranted, the collection device provides satisfactory sensitivity. Hence, whenever blood sampling is not possible, the Dräger DCD 5000 collection device offers a good tool for the analysis of synthetic cannabinoids in oral fluid in the broad field of drug testing. Copyright © 2012 John Wiley & Sons, Ltd.
Regulation of the specialized DNA polymerase eta: Revisiting the biological relevance of its PCNA‐ and ubiquitin‐binding motifs
Authors: Despras Emmanuelle , Delrieu Noémie , Garandeau Charlène , Ahmed‐Seghir Sana , Kannouche Patricia L.
Published: October 2012

During translesion synthesis (TLS), low‐fidelity polymerases of the Y‐family polymerases bypass DNA damages that block the progression of conventional processive DNA polymerases, thereby allowing the completion of DNA replication. Among the TLS polymerases, DNA polymerase eta (polη) performs nucleotide incorporation past ultraviolet (UV) photoproducts and is deficient in cancer‐prone xeroderma pigmentosum variant (XPV) syndrome. Upon UV irradiation, the DNA sliding clamp PCNA is monoubiquitylated on its conserved Lys‐164. This event is considered to facilitate the TLS process in vivo since polη preferentially interacts with monoubiquitylated PCNA through its ubiquitin‐binding domain (UBZ) as well as its PCNA interacting peptide (PIP)‐box. However, recent observations questioned this model. Therefore, in this study, we re‐examined the relative contribution of the regulatory UBZ and PIP domains of polη in response to UVC. We show that simultaneous invalidation of both motifs confers sensitivity to UVC, sensitization by low concentrations of caffeine, prolonged inhibition of DNA synthesis and persistent S phase checkpoint activation, all characteristic features of XPV cells. While each domain is essential for efficient accumulation of polη in replication factories, mutational inactivation of UBZ or PIP motif only confers a slight sensitivity to UVC indicating that, although informative, polη focus analysis is not a reliable tool to assess the polη's ability to function in TLS in vivo. Taken together, these data indicate that PIP and UBZ motifs are not required for recruitment but for retention of polη at sites of stalled replication forks. We propose that this is a way to ensure that a sufficient amount of the protein is available for its bypass function. Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.
Safety Behaviours in Eating Disorders: Factor Structure and Clinical Validation of the Brief Safety Behaviours Scale
Authors: Waller Glenn , Kyriacou Marcoulides Olivia
Published: October 2012

This study examined the utility of a transdiagnostic measure of safety behaviours [Brief Safety Behaviours Scale (BSBS)] in eating disorders. Prior to treatment, a group of 102 women with eating disorders completed the BSBS and well‐validated measures of eating pathology, anxiety and intolerance of uncertainty. The BSBS had three factors, suggesting that avoidant, checking and social safety behaviours are distinct constructs in the eating disorders. This three‐scale scoring system showed greater clinical precision in correlations with eating pathology than the original two‐scale version. The pattern of safety behaviours in the eating disorders is more specific than had previously been shown in other clinical samples. While it is important to consider eating‐related safety behaviours in the eating disorders (e.g. restriction, body checking), it is also necessary to consider the role of generic safety behaviours when assessing, formulating and treating eating disorders. Copyright © 2012 John Wiley & Sons, Ltd and Eating Disorders Association.
Long‐range transcriptional regulation of breast cancer genes
Authors: Betts Joshua A. , French Juliet D. , Brown Melissa A. , Edwards Stacey L.
Published: October 2012

Breast cancer is a major health problem and understanding the genetic basis of this disease is crucial for predicting risk and developing effective targeted therapeutics. Several breast cancer predisposing genes have been identified, but mutations in the coding regions of these genes only accounts for a small proportion of risk. Research now suggests that combinations of multiple non‐coding changes in breast cancer susceptibility genes, which cause moderate alterations in gene expression, will be responsible for the remaining inherited risk. These non‐coding changes will include variants in proximal and distal transcriptional and post‐transcriptional regulatory elements and may affect the levels and function of trans‐acting factors, including proteins and RNAs, which act on these elements. Somatic changes in such elements and factors have also been associated with breast cancer progression. With the recent advent of techniques allowing the detection of long‐range DNA interactions spanning the human genome, it has become increasingly clear that long‐range regulatory elements constitute an important mechanism for gene regulation. Recent studies have identified several such elements that are important for regulating genes involved in breast cancer, raising the possibility that defects in these sequences may contribute to breast cancer predisposition and progression. In this review, we discuss the emerging functions of cis‐regulatory elements and a subset of trans‐acting factors in breast tumorigenesis. We also discuss some recent progress in our understanding of how dysregulation in these transcriptional components may contribute to breast cancer, and the potential implications for molecular diagnosis, prognosis prediction, and the treatment of this disease. © 2012 Wiley Periodicals, Inc.
Recruitment of a Myeloid Cell Subset (CD11b/Gr1mid) via CCL2/CCR2 Promotes the Development of Colorectal Cancer Liver Metastasis
Authors: Zhao Lei , Lim Su Yin , Gordon-Weeks Alex N. , Tapmeier Thomas T. , Im Jae Hong , Cao Yunhong , Beech John , Allen Danny , Smart Sean , Muschel Ruth J.
Published: October 2012

Liver metastasis from colorectal cancer is a leading cause of cancer mortality. Myeloid cells play pivotal roles in the metastatic process, but their prometastatic functions in liver metastasis remain incompletely understood. To investigate their role, we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells. Among the heterogeneous myeloid infiltrate, we identified a distinct population of CD11b/Gr1mid cells different from other myeloid populations previously associated with liver metastasis. These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2. Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets. Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1mid recruitment and decreased tumor burden. Depletion of the CD11b/Gr1mid subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation. There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1mid cells. Additionally, an analogous myeloid subset was found in liver metastases of some colorectal cancer patients.

Conclusion:

Collectively, our findings highlight the importance of myeloid cells—in this case a selective CD11b/Gr1mid subset—in sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy.
Anemia during treatment with peginterferon Alfa-2b/ribavirin and boceprevir: Analysis from the serine protease inhibitor therapy 2 (SPRINT-2) trial
Authors: Sulkowski Mark S. , Poordad Fred , Manns Michael P. , Bronowicki Jean-Pierre , Rajender Reddy K. , Harrison Stephen A. , Afdhal Nezam H. , Sings Heather L. , Pedicone Lisa D. , Koury Kenneth J. , Sniukiene Vilma , Burroughs Margaret H. , Albrecht Janice K. , Brass Clifford A. , Jacobson Ira M.
Published: October 2012

Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb] <10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had ≥1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354,

P

< 0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use.

Conclusion
: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation. (Hepatology 2013)
The Postbinding Activity of Scavenger Receptor Class B Type I Mediates Initiation of Hepatitis C Virus Infection and Viral Dissemination
Authors: Zahid Muhammad N. , Turek Marine , Xiao Fei , Dao Thi Viet Loan , Guérin Maryse , Fofana Isabel , Bachellier Philippe , Thompson John , Delang Leen , Neyts Johan , Bankwitz Dorothea , Pietschmann Thomas , Dreux Marlène , Cosset François-Loïc , Grunert Fritz , Baumert Thomas F. , Zeisel Mirjam B.
Published: October 2012

Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor highly expressed in the liver and modulating HDL metabolism. Hepatitis C virus (HCV) is able to directly interact with SR-BI and requires this receptor to efficiently enter into hepatocytes to establish productive infection. A complex interplay between lipoproteins, SR-BI and HCV envelope glycoproteins has been reported to take place during this process. SR-BI has been demonstrated to act during binding and postbinding steps of HCV entry. Although the SR-BI determinants involved in HCV binding have been partially characterized, the postbinding function of SR-BI remains largely unknown. To uncover the mechanistic role of SR-BI in viral initiation and dissemination, we generated a novel class of anti–SR-BI monoclonal antibodies that interfere with postbinding steps during the HCV entry process without interfering with HCV particle binding to the target cell surface. Using the novel class of antibodies and cell lines expressing murine and human SR-BI, we demonstrate that the postbinding function of SR-BI is of key impact for both initiation of HCV infection and viral dissemination. Interestingly, this postbinding function of SR-BI appears to be unrelated to HDL interaction but to be directly linked to its lipid transfer function.

Conclusion:

Taken together, our results uncover a crucial role of the SR-BI postbinding function for initiation and maintenance of viral HCV infection that does not require receptor-E2/HDL interactions. The dissection of the molecular mechanisms of SR-BI–mediated HCV entry opens a novel perspective for the design of entry inhibitors interfering specifically with the proviral function of SR-BI.
Aging promotes the development of diet-induced murine steatohepatitis but not steatosis
Authors: Fontana Luis , Zhao Enpeng , Amir Muhammad , Dong Hanqing , Tanaka Kathryn , Czaja Mark J.
Published: October 2012

The prevalence of the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in humans increases with age. It is unknown whether this association is secondary to the increased incidence of risk factors for NAFLD that occurs with aging, reflects the culmination of years of exposure to lifestyle factors such as a high-fat diet (HFD), or results from physiological changes that characterize aging. To examine this question, the development of NAFLD in response to a fixed period of HFD feeding was examined in mice of different ages. Mice aged 2, 8, and 18 months were fed 16 weeks of a low-fat diet or HFD. Increased body mass and insulin insensitivity occurred in response to HFD feeding irrespective of the age of the mice. The amount of HFD-induced hepatic steatosis as determined biochemically and histologically was also equivalent among the three ages. Liver injury occurred exclusively in the two older ages as reflected by increased serum alanine aminotransferase levels, positive terminal deoxynucleotide transferase–mediated deoxyuridine triphosphate nick end-labeling, and caspase activation. Older mice also had an elevated innate immune response with a more pronounced polarization of liver and adipose tissue macrophages into an M1 phenotype. Studies of cultured hepatocytes from young and old mice revealed that aged cells were selectively sensitized to the Fas death pathway.

Conclusion
: Aging does not promote the development of hepatic steatosis but leads to increased hepatocellular injury and inflammation that may be due in part to sensitization to the Fas death pathway and increased M1 macrophage polarization. (Hepatology 2013)
β-catenin regulates innate and adaptive immunity in mouse liver ischemia-reperfusion injury
Authors: Ke Bibo , Shen Xiu-Da , Kamo Naoko , Ji Haofeng , Yue Shi , Gao Feng , Busuttil Ronald W. , Kupiec-Weglinski Jerzy W.
Published: October 2012

Dendritic cells (DCs) are critical mediators of immune responses that integrate signals from the innate immune system to orchestrate adaptive host immunity. This study was designed to investigate the role and molecular mechanisms of STAT3-induced β-catenin in the regulation of DC function and inflammatory responses

in vitro

and

in vivo
. STAT3 induction in lipopolysaccharide (LPS)-stimulated mouse bone marrow-derived DCs (BMDCs) triggered β-catenin activation by way of GSK-3β phosphorylation. The activation of β-catenin inhibited phosphatase and tensin homolog delete on chromosome 10 (PTEN) and promoted the phosphoinositide 3-kinase (PI3K)/Akt pathway, which in turn down-regulated DC maturation and function. In contrast, knockdown of β-catenin increased PTEN/TLR4 (Toll-like receptor 4), interferon regulatory factor-3 (IRF3), nuclear factor kappa B (NF-κB) activity, and proinflammatory cytokine programs in response to LPS stimulation. In a mouse model of warm liver ischemia and reperfusion injury (IRI), disruption of β-catenin signaling increased the hepatocellular damage, enhanced hepatic DC maturation/function, and PTEN/TLR4 local inflammation

in vivo.

Conclusion
: These findings underscore the role of β-catenin to modulate DC maturation and function at the innate-adaptive interface. Activation of β-catenin triggered PI3K/Akt, which in turn inhibited TLR4-driven inflammatory response in a negative feedback regulatory mechanism. By identifying the molecular pathways by which β-catenin regulates DC function, our findings provide the rationale for novel therapeutic approaches to manage local inflammation and injury in IR-stressed liver. (Hepatology 2013)
Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b
Authors: Kim Jeong Kyu , Noh Ji Heon , Jung Kwang Hwa , Eun Jung Woo , Bae Hyun Jin , Kim Min Gyu , Chang Young Gyoon , Shen Qingyu , Park Won Sang , Lee Jung Young , Borlak Jürgen , Nam Suk Woo
Published: October 2012

Sirtuins are nicotinamide adenine dinucleotide oxidized form (NAD+)-dependent deacetylases and function in cellular metabolism, stress resistance, and aging. For sirtuin7 (SIRT7), a role in ribosomal gene transcription is proposed, but its function in cancer has been unclear. In this study we show that SIRT7 expression was up-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients. SIRT7 knockdown influenced the cell cycle and caused a significant increase of liver cancer cells to remain in the G1/S phase and to suppress growth. This treatment restored p21WAF1/Cip1, induced Beclin-1, and repressed cyclin D1. In addition, sustained suppression of SIRT7 reduced the

in vivo

tumor growth rate in a mouse xenograft model. To explore mechanisms in SIRT7 regulation, microRNA (miRNA) profiling was carried out. This identified five significantly down-regulated miRNAs in HCC. Bioinformatics analysis of target sites and ectopic expression in HCC cells showed that miR-125a-5p and miR-125b suppressed SIRT7 and cyclin D1 expression and induced p21WAF1/Cip1-dependent G1 cell cycle arrest. Furthermore, treatment of HCC cells with 5-aza-2′-deoxycytidine or ectopic expression of wildtype but not mutated p53 restored miR-125a-5p and miR-125b expression and inhibited tumor cell growth, suggesting their regulation by promoter methylation and p53 activity. To show the clinical significance of these findings, mutations in the DNA binding domain of

p53

and promoter methylation of miR-125b were investigated. Four out of nine patients with induced SIRT7 carried mutations in the

p53

gene and one patient showed hypermethylation of the miR-125b promoter region.

Conclusion
: Our findings suggest the oncogenic potential of SIRT7 in hepatocarcinogenesis. A regulatory loop is proposed whereby SIRT7 inhibits transcriptional activation of p21WAF1/Cip1 by way of repression of miR-125a-5p and miR-125b. This makes SIRT7 a promising target in cancer therapy. (Hepatology 2013)
Osteopontin promoter polymorphisms at locus -443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma
Authors: Dong Qiong-Zhu , Zhang Xiao-Fei , Zhao Yue , Jia Hu-Liang , Zhou Hai-Jun , Dai Chun , Sun Hai-Jing , Qin Yi , Zhang Wei-De , Ren Ning , Ye Qing-Hai , Qin Lun-Xiu
Published: October 2012

Osteopontin (OPN) plays a crucial role in hepatocellular carcinoma (HCC) metastasis. However, little is known about the impact of OPN polymorphisms on cancer progression. In this study, we first identified the single nucleotide polymorphisms (SNPs) in the OPN promoter region by direct sequencing in 30 HCCs, and then evaluated the prognostic values of the selected ones in two large cohorts of 826 HCC patients. The identified SNPs were functionally analyzed using

in vitro

and

in vivo

assays and their correlations with OPN levels were also evaluated. Only SNP at locus -443 and their related haplotypes (Ht2: -1748A/-616G/-443T/-155* [*indicates base deletion]; Ht3: -1748A/-616G/-443C/-155*) were significantly associated with overall survival (OS) and time to recurrence (TTR). The patients with the -443TT/TC genotype or Ht2 had a shorter OS and TTR compared with those with -443CC genotype or Ht3. This was further confirmed in the validation cohort. Moreover, this correlation remained significant in patients with small HCCs (≤5 cm). Multivariate analyses indicated that the prognostic performance of the -443 genotypes (OS,

P

= 0.031; TTR,

P

= 0.005) and their related haplotypes (OS,

P

= 0.002; TTR,

P

= 0.001) was independent of other clinicopathological factors. The Ht2 and -443TT genotype could significantly increase the promoter transcriptional activity and expression level of OPN compared with the Ht3 or -443CC genotype, and lead to an obvious increase in both

in vitro

invasion and

in vivo

tumor growth and lung metastasis of HCC cells (

P

< 0.05).

Conclusion
: The genetic variation at locus -443 of the OPN promoter plays important roles in the regulation of OPN expression and cancer progression of HCCs, which is a novel determinant and target for HCC metastasis and prognosis. (Hepatology 2013)